Scand J Gastroenterol 1992;27:897-906.

REVIEW

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Cytokines in Inflammatory Bowel Disease The etiology of inflammatory bowel disease (1BD)-that is, ulcerative colitis (UC) and Crohn’s disease (CD)-remains unknown. Although there is increasing evidence, both from in vitro (1) and in vivo investigations ( 2 4 ) , that immunologic factors play a pathogenic role, the precise mechanisms are not well defined. Cytokines are proteinaceous mediators, produced by leukocytes and other cells, which participate in immunoinflammatory reactions (5). Cytokines are active at concentrations from to 10-’M. Most cytokines have paracrine functions, but some cytokines act also in autocrine and endocrine fashions. As summarized in Table I, these peptides comprise an increasing number of important immunologic mediators, which may be pertinent to IBD. This review will focus in more detail on the possible pathogenic role of some of these cytokines in IBD, particularly interleukin (1L)-1, IL-2, IL-6, IL-8, tumor necrosis factor a (TNF-a), and interferon-y (IFN-y). Furthermore, we shall discuss their interaction with other inflammatory mediators and the effect of drugs used in the treatment of IBD on production and function of cytokines. IL-1 IL-1 is produced primarily, but not exclusively, by macrophages/monocytes (Mq5) and consists of at least two 17kDa polypeptides (IL-la and P), which are involved in a wide spectrum of immunoinflammatory activities. These include fever, wasting, increased vascular permeability, leukocytosis, lowering of plasma levels of iron and zinc, induction of hepatic acute-phase protein synthesis, release of proinflammatory mediators such as histamine, plasminogen, platelet-activating factor (PAF), eicosanoids, collagen, and collagenase, and induction of free oxygen radical production. IL-1 also plays a crucial role in antigen-dependent T-cell activation by providing an essential costimulatory signal for these cells to produce lymphokines, particularly B-cell growth factors such as IL-2, IL-4, IL-5, IL-6, and IFN-y (6). In patients with active IBD the production of IL-1 by isolated blood mononuclear cells (BMC) in vitro has been found to be normal (7) or increased, using bioassay or enzyme-linked immunosorbent assay (ELISA) (8-10). At the mucosal level both an increased spontaneous and a lipopolysaccharide (LPS)-induced production of IL-lP have consistently been demonstrated in vitro with mucosal mononuclear cells (MMC) isolated from surgically removed bowel

segments from patients with active IBD. A decline in IL-lP production after Mq5 depletion with a monoclonal antibody suggests that M$ are the major source of IL-1 in IBD mucosa (11). Further studies, using endoscopic mucosal biopsy specimens, confirmed these findings (12, 13) and showed that elevated mucosal values of IL-1P correlate with the degree of histologic activity (12). Increased mucosal IL-1 values have also been demonstrated in animal models of colitis, and IL-lP expression by basal crypt enterocytes led to the suggestion that there may be other cellular sources than Mq5 of this monokine in inflamed gut mucosa (14, 15). In contrast, IBD sera seem to lack significant IL-1 activity as measured by both bioassay (8) and ELISA (16). Using the mouse thymocyte bioassay, sera of patients with CD were recently demonstrated to contain substantial amounts of circulating, apparently IL-I-specific inhibitors (16). The nature of these inhibitor(s) is unknown, but several more or less specific inhibitors of I L - l a and IL-lP have recently been described (17, 18). For example, high-avidity antibodies to IL-6 and IL-a, but not to IL-lP, have been demonstrated in sera from healthy individuals (18). An IL-1 receptor antagonist (IRAP or IL-ha), acting at the target cell level, has also been demonstrated in sera (19, 20) and in urine samples (21-23) from normal subjects and in increased amounts in these body fluids during febrile conditions (2125). IRAP is structurally closely related to IL-la and IL-1P and appears to be the evolutionarily oldest member of the IL-1 family (26). Taken together, these data indicate that increased IL-1 production/release occurs both in vitro and in vivo at the mucosal level in patients with active IBD. Although there is yet no evidence of a direct pathogenic effect of IL-1 in IBD, increased IL-1 values may contribute at several levels to the chronic inflammation in IBD, including the initiation and perpetuation of local T-cell-mediated immune processes (2, 3). IL-1 itself is cytotoxic to islets of Langerhans (27), cytostatic to melanocytes and other tumor cells (28), and arthritogenic in rat and rabbit models (29). A similar damaging effect of IL-1 on intestinal mucosal cells may contribute to mucosal damage in IBD in combination with other cytokines (30). IL-2 IL-2 is a 15-kDa polypeptide produced exclusively by lymphocytes. It functions as an obligatory signal for T- and B-

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Table I. Clinically important human inflammatory cytokines Acronym

Producers

Mol. weight (kDa)

Major functions Activate: T-, B-, and NK cells Polymorphonuclear cells Endothelial cells Nerve cells Adipocytes Chondrocytes, osteoclasts, and fibroblasts Thyrocytes and pancreatic /3-cells Hepatocytes Cytotoxic: Melanocytes Pancreatic /3-cells (intermediate conc.) In viuo effects: Fever, anorexia, slow-wave sleep Acute-phase protein induction Insulin, ACTH, cortisol induction Leukocytosis Radioprotection Promote: T- and B-cell growth NK-cell growth Activate: Hemopoetic cells, mast cells Promote: T- and B-cell growth Promote: Eosinophil differentiation As IL-1 (few exceptions)

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~~

IL-la IL-l/3

Monocytes-macrophages NK cells B cells Dendritic cells Langerhans cells Keratinocytes Endothelial cells Epithelial cells Astrocytes Mesangial cells Fibroblasts Synovial cells Smooth-muscle cells

17

IL-2

T cells

15

IL-3

T cells

15-28

IL-4

T cells

12-20

IL-5

T cells

20-60

IL-6

Monocytes-macrophages (see also IL-1) Cardiac myxoma cells Thyrocytes and pancreatic islet cells Neoplastic cells: myelomas, osteosarcomas, renal and lung carcinomas, astrocytornas Blood mononuclear cells Fibroblasts Keratinocytes Endothelial cells Neoplastic cells Th2 cells B cells Mast cells

20-30

TNF-a

Monocytes/macrophages T cells Keratinocytes

17-50

TNF-/3/LT

T cells

17-180

IFN-al/-Cu2 (>20 subtypes)

Leukocytes

18-26

IFN-/3 (=IFN-P,)

Many cells (virus-infected)

IFN-./

T cells

IL-8

IL-10

10

30-35

22 20-25

Chemotactic for: Neutrophils T lymphocytes Monocytes Activates: T, cells and thymocytes (only with IL-2) Mast cells Inhibits: IFN-y production by T cells Activates: Lymphocytes Neutrophils, eosinophils Endothelial cells Fibroblasts, chondrocytes Osteoclasts Nerve cells Cytotoxic: Transformed and virus inf. cells AS TNF-a Activate: NK and B cells + other cells Antiviral activity Activates: NK cells Antiviral activity Activates: Monocytes/macrophages, fibroblasts T, and B cells (different) MHC class I1 expression Inhibits: General growth of cells Viral replication (weak)

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cell growth by interacting with a specific receptor complex (IL-2R) on T cells and B cells (31, 32). Decreased or absent IL-2 production by active IBD BMC (7,33), MMC (34, 35), or both (36) has been demonstrated in vitro. Inflamed IBD mucosa lacks natural killer (NK) cell activity (37), and both BMC (38) and MMC challenged with optimal amounts of IL-2 have normal lymphokine-activated killer (LAK) activity (37). These findings have led to the suggestion that insufficient production of IL-2 leads to local immune abnormalities (35), including defective T-cell functions in IBD (33, 36). This is, however, difficult to reconcile with the clinical experience that a defective cellular immunity may lead to opportunistic infections and, ultimately, to the acquired immunodeficiency syndrome. In fact, remission of active CD has anecdotally been reported during human immunodeficiency virus infection (39), and active CD responds to rather than deteriorates during treatment with cyclosporin A (CsA), a potent inhibitor of IL-2 production (2,3). The normal production of IL-2 by both BMC (2) and MMC (35) in patients with inactive IBD also makes a primary defect less likely. Several factors have been proposed to account for the reduced IL-2 production observed in vitro in certain active chronic immunoinflammatory diseases (40). Among these, a deficient IL-1 production in vivo or an abnormality in the mucosal T-helper to T-suppressor ratio seems to be less pertinent to IBD (41-43). The same applies to the putative suppressive role of prostaglandins (PG) and IL-2 inhibitors (35). The apparent low IL-2 production in vitro seems to be explained by neither exhaustion of the cells nor increased absorption (35). As discussed elsewhere (12), the results obtained in vitro using isolated cells in culture may not necessarily be representative of the pathogenic mechanisms that operate in vivo in IBD. The advent of a specific ELISA has facilitated the measurement of IL-2 and its receptor (IL-2R) in IBD patients. Other studies, using ELISAs for IL-2, have shown that conditions characterized by enhanced T-cell-mediated immunity in vivo, such as transplant rejection (44, 45) and certain chronic immunoinflammatory disorders (46,47), are associated with increased plasma levels of IL-2. Significantly increased concentrations of IL-2 in both plasma and endoscopic mucosal biopsy specimens could also be demonstrated in patients with active IBD (12, 48). Furthermore, recent experiments, using the polymerase chain reaction (PCR), have substantiated these observations by demonstrating the presence of increased mucosal T-cell IL-2 mRNA transcripts in IBD (49). The human IL-2R consists of a low-affinity (55-kDa) molecule and an intermediate-affinity (75-kDa) molecule, which form a dimeric, biologically active high-affinity IL-2R complex (31, 32, 50-53). The 55-kDa (Tac receptor) may be released/shed from activated T cells in a soluble form (sIL2R). Increased concentrations of sIL-2R in plasma or serum and urine have been demonstrated in clinical conditions

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characterized by T-cell activation in vivo, such as renal (44, 54) and liver transplant rejection (559, T-cell leukemia (56), and certain chronic immunoinflammatory disorders (47, 57, 58). Significantly increased serum concentrations of s I L - ~ R , which correlate with plasma orosomucoid concentrations and disease activity, have consistently been demonstrated in IBD patients (48, 59-61). Recently, increased sIL-2R levels have also been detected in endoscopic mucosal biopsy specimens from patients with active IBD (12, 60). This is in accordance with previous in vitro studies on BMC and MMC showing increased expression of the cellular IL-2R (62, 64) and other activation antigens, such as the transferrin receptor, MHC class I1 molecules, and adhesion moleculesthat is, the lymphocyte function-associated antigen-1 (LFA1) and its ligand, the intracellular adhesion molecule-1 (ICAM-1) (65). LFA-1, ICAM-1, and other adhesion molecules are important for the interaction between activated immune cells because they traverse the cell membranes and provide linkages between the extracellular and intracellular matrices of the involved cells ( 5 ) . The precise source of sIL-2R in active IBD is not known, as activated B cells (66), M$J, and NK cells (62) also express IL-2R. MMC from patients with CD, but not UC, secrete spontaneously increased amounts of sIL-2R in vitro and have been proposed to account for the increased serum values (67). The precise function of sIL-2R is also not known. SIL-2R binds IL-2 and has therefore been proposed to play a role as a downregulator of T-cell functions (68). This proposal appears rather unlikely, however, considering the very low affinity of sIL-2R to its natural ligand (69). IL-6 IL-la, IL-lP, and TNF are all potent inducers of IL-6 in both M@ and T cells (69). IL-6 may act as an important second messenger of IL-1 and TNF. IL-6 plays a key role in the acute-phase response by inducing increased acute-phase protein synthesis in hepatocytes (6). Furthermore, IL-6 stimulates T and B cells, most likely because it increases the responsiveness of these cells to IL-2 (70). Several studies have dealt with IL-6 in IBD (71-75). However, elevated serum and mucosal levels have been reported (72,73,75). Although serum concentrations of IL6 do not correlate with clinical activity in CD, they correlate, as expected, with acute-phase protein levels. Because of the short half-life of IL-6 (5 min), the increased serum values have been proposed to reflect a continuous stimulation of IL-6-producing cells (754, probably M$J (74). Both circulating and mucosal IL-6 levels may reflect the degree of disease activity and the extent of pathologically affected areas. IL-8 Increased polymorphonuclear (PMN) cell chemotaxis is an

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important feature of the inflammatory process, and large numbers of PMN accumulate initially in the inflamed intestinal mucosain IBD (76). Leukotriene (LT) Bd, complement split products CSa,the bacterial product formyl-methionylleucyl-phenylalanine (fMLP), and interleukin-8/neutrophil activating peptide-1 (IL-8/NAP-1) are all likely to provide migratory stimuli in IBD. IL-8 is a potent chemoattractant for PMN, but in contrast to LTB,, C5a,and fMLP, it has limited effects on MG. The IL-8 gene was first described in MG, but it is also found in other cells, including PMN (77, 78). IL-8 is a member of a family of chemoattractants sometimes termed the hematopoietic or intercrine family of molecules (79). The precise role of IL-8 in IBD is unknown. Elevated IL8 concentrations have been found in intestinal specimens, but not in plasma, from patients with active UC (80). In addition to its chemotactic potential, IL-8 is capable of activating PMN degranulation (81), respiratory burst (82), and 5-lipoxygenase activation but not the release of arachidonic acid (83) or the release of intracellular CaZ+(84).

TNF TNF-a and p are 17-kDa polypeptides whose genes are located in the major histocompatibility complex (MHC) region in experimental animals and man (85-86). Linkage disequilibrium with polymorphic TNF-a genes and certain HLA-DR types has been demonstrated (87-89). Because TNF-a alleles furthermore appear to be associated with a low TNF-a production, it has been suggested that the association of specific HLA types with certain immunoinflammatory diseases may be explained by high- or lowTNF-a responder status (6, 87). However, no such associations with HLA types have been found in IBD (90). TNF-a and -p induce fever, increased acute-phase protein synthesis, and endothelial cell activation, all of which are of paramount importance in several types of septic shock conditions (91). Activated MG produce TNF-a, and activated T cells produce both forms of TNF. TNF-LUand TNF-p are potent coactivators of T and B cells (92). Although TNF-a shares many activities with IL-1, TNF-(Uhas no structural relation to IL-1, and it binds to different receptors. Elevated circulating and local TNF-a concentrations have been found in many infectious and non-infectious conditions, characterized by MG and/or T-cell-mediated injury, such as renal allograft rejection. However, several studies have failed so far to show significant differences in serum or mucosal TNF-LYlevels between IBD patients and controls (10,93,94). However, it has been proposed that the amount of TNF-LUin stools may be a marker of intestinal inflammation (95). At present, the precise pathogenic role of TNFLU or TNF-p in IBD is unclear.

IFN-y IFN-y is a lymphokine that acts as a potent activator of M@ (5). IFN-y has a molecular mass of 20-25 kDa; it is produced by T cells and activates several important inflammatory cells. The spontaneous release of IFN-y by cultured C D MMC has been found to be increased, whereas BMC only release IFN-)I after stimulation (96). It has been suggested that C D MMC are stimulated in vivo to produce IFN-y. Although this conflicts with other reports showing normal (97) or even decreased production of IFN-y by isolated IBD MMC, the discrepancy may reflect methodologic differences (35, 98). IFN-y may have a role in cell interactions in the lamina propria and contribute to the locally occurring immune phenomena in CD, particularly by increasing MG and epithelial cell expression of MHC class-I1 antigens (99). PHARMACOLOGIC EFFECTS ON CYTOKINE PRODUCTION AND ACTION O F SULFASALAZINE AND ITS METABOLITES 5-Aminosalicylic acid (5-ASA), but not sulfasalazine, has been shown to reduce the production of IL-1p by cultured inflamed IBD colonic mucosa biopsy specimens (100). In contrast, sulfasalazine inhibited the production or release of IL-1 and IL-6 by MG in vitro, whereas no such effect was found for 5-ASA or sulfapyridine at pharmacologically relevant concentrations (0.025-0.25 mM) (101). It is obscure why the biologically active component of sulfasalazine, 5-ASA, does not have an effect in this system. Sulfasalazine has also been shown to inhibit IL-2 production of cultured splenocytes, whereas 5-ASA and sulfapyridine failed to affect the production of this cytokine (102). Furthermore, both the alloantigen- and mitogen-stimulated proliferative responses were dose-dependently inhibited by sulfasalazine in the concentration range 0.01-0.5 mM, whereas 5-ASA and sulfapyridine again were without effect (102). Sulfasalazine, but not 5-ASA or sulfapyridine, has also been shown to inhibit the binding of TNF-ato its specific cell receptors (103). Furthermore, sulfasalazine inhibits TNF-(E. production (104). No current information is available dealing with sulfasalazine or its metabolites on IL-8 or IFN-y production. EFFECTS OF GLUCOCORTICOIDS ON CYTOKINES The anti-inflammatory activity of glucocorticoids (GC) is dependent on regulation of protein synthesis. GC control protein synthesis through formation of a complex with cytoplasmic receptors in target cells that, after modification, bind to specific regions of DNA known as the steroid response elements (SRE). The genes coding for GC hormone receptors belong to a superfamily of genes encoding also the thyroid, vitamin D, and retinoic acid receptors. Binding of

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Review

the GC-receptor complex to SRE may evoke either a downregulatory or an upregulatory signal of gene transcription. For example, GC inhibit the transcription of the prolactin gene (105) and stimulate the production of lipocortin, a member of the annexin peptide family, which potently inhibits the activity of phospholipase A2 (106). This enzyme is responsible for the release of arachidonic acid, the precursor of PG and LT, and for the formation of PAF. These are all important mediators of inflammatory reactions, not only by their intrinsic pharmacologic activity but also by their indirect actions exerted through interaction with cytokine production and function. Therefore, the GC-stimulated production of lipocortin is likely to play a role in the antiinflammatory activity of this group of drugs. Some of the cytokines are also under direct control of GC at the level of gene transcription. Thus, GC inhibit the production of IL-1 by MC#J(107) and human BMC (108,109), thereby interfering with activation of T lymphocytes. They further inhibit transcription of the IL-2 gene in T cells and attenuate the IL-Zmediated receptor activation of these cells (110). Some of these effects may be secondary to inhibition of LTB4 formation (111). They also inhibit the production of IFN-y mRNA in human T cells (112) and the adjuvant effect of IFN-y in processing and presentation of antigens (113). Finally, the inhibitory effects of GC on IL-3 expression by murine T lymphocytes (114), on the enhancement by IL-3, IL-5, granulocyte/macrophage colony-stimulating factor (GM-CSF), and IFN-y of eosinophil survival (115), on stimulated or non-stimulated IL-6 production by peripheral blood monocytes from patients with CD (116), and on IL-8 gene activation (117) have recently been described. GC thus have a wide range of potent regulatory activities in both production and function of a plethora of cytokines that are involved in immunoinflammatory reactions. This may readily explain the beneficial effects of these drugs in the treatment of IBD. EFFECT O F CYCLOSPORIN A ON CYTOKINES AND T-CELL ACTIVATION Both CsA and the recently introduced macrolide immunosuppresants FK506 and rapamycin bind to and inhibit the peptidyl-prolyl isomerase activity (PPIase) of their respective cytosolic binding proteins-that is, cyclophilin and FK binding protein. PPIase is important for the folding of proteins in their native conformations and may be involved in the regulation of intracellular signaling events in T cells (118, 119). Although the precise mechanism involved is not completely understood, inhibition of T cell, mainly T helper cell (CD4+), and IL-2 transcription (120) and production (121) is the key immunosuppressive effect of CsA; however, the release of other lymphokines, such as IFN-y (122) and IL-4 (123), is also affected. In contrast, suppressor/cytotoxic T cells (CD8+) are rela-

90 I

tively resistant to CsA (124), perhaps owing to a less IL-2dependent or alternative activation pathway. The putative therapeutic effect of CsA in IBD ( 2 , 3) has recently been substantiated by the demonstration that in situ stimulation of mucosal T cells in explant cultures of human fetal colon tissue results in epithelial damage and that this process is inhibited by CsA (125). The CsA-induced imbalance between helper and suppressor T-cell subsets may tip the balance towards immunologic tolerance (126). INTERACTIONS WITH OTHER INFLAMMATORY MEDIATORS Cytokine interactions with lipid inflammatory mediatorsthat is, PG, LT, hydroxyeicosatetraenoic acids (HETE), and PAF-have been reported in various inflammatory reactions in vitro and in vivo. Most notably, PGE2has been identified as an endogenous inhibitor of IL-1, probably mediated by an increased intracellular level of cyclic AMP (127). Furthermore, the proliferative response of lymphocytes to IL-1 is inhibited by PGE2 (128), which thus may act as a functional IL-1 antagonist. By culturing rnurine spleen cells in the presence of dextran beads, it is possible to induce granulomas in vitro; the formation of such granulomas is stimulated by IL-1 and TNF-aand suppressed by PGE2, IL-4, and IFN-y, indicating a multifactorial control consisting of both pro-inflammatory and anti-inflammatory signals elaborated by spleen cells (129). It is thus evident that PGE2 antagonizes the proinflammatory activity of IL-1 and TNF-a in this model. Piroxicam, a non-steroidal anti-inflammatory drug (NSAID), has been shown to increase the activity of lymphoproliferative cytokines by mononuclear cells in vitro (130), and NSAIDs may therefore modulate the immune functions by suppressing the formation of the endogenous cytokine inhibitor, PGE2. The downregulatory activity of PGE2 on IL-1 synthesis constitutes a negative feedback signal to suppress further production of IL-1, since IL-1 is a potent enhancer of PGE2 synthesis (131). In addition, PGs of the E series also suppress IL-2 production by murine (132) and normal human peripheral blood lymphocytes (133). The human recombinant IL-la-induced increase in PG and thromboxane release from human blood M$ is antagonized by IFN-a and IFN-y (134), and IL-1 and IFNs thus appear to have antagonistic effects on PG production by monocytes. IL-4 potently suppresses the increased levels of TNF-a, IL-1, and PGE2 in cells stimulated with lipopolysaccharide with or without IFN-y and is an endogenous inhibitor of PGE, synthesis in M$, possibly by inhibiting the gene transcription of TNF-a and IL-1 (135). I L - l a and IL1/3 are equipotent in stimulating rabbit synovial fibroblasts and articular chondrocytes to synthesize PGE2when injected intra-articularly into the knee joint (136). This injection causes accumulation of inflammatory leukocytes in the syn-

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ovial lining and joint cavity. PGE2 is a local mediator in the brain of the pyrogenic effect of IL-1 (69, 131). It may also mediate anorexia associated with IL-1 and TNF-a release during inflammatory and infectious diseases, since the anorexigenic effect of IL-1 in rats is abolished by pretreatment with ibuprofen (137). I L - l a and IL-1p are equally effective in inducing the release of PGE2 from human skin fibroblasts in vitro (138). IL-la, IL-lp, and TNF-(Yplay an important role in connective tissue destruction, and this destruction is at least in part mediated by the induction of PGE2 release. However, IL-1-induced PGE2 production by fibroblasts and synovial cells is significantly inhibited by IL-6, whereas IL-6 stimulates TNF-a-induced PGEz production (139). IL-6 thus seems to modulate the formation of PGE2 in response to pro-inflammatory cytokines in a bidirectional manner. In vitro studies have indicated that 5-lipoxygenase products (LT and HETE) promote the production of TNF-a by activated M@. This suggests that 5-lipoxygenase inhibitors suppress not only the formation of pro-inflammatory LTs but also the production of TNF-a, which may play a key role in the generation of other cytokines contributing to the pathology of IBD. However, in a rat model of inflammation (the air pouch), various 5-lipoxygenase inhibitors with different mechanisms of action were shown to inhibit the formation of LTs and at the same time enhance TNF-a production (140). These results do not support a role for 5lipoxygenase products in the regulation of TNF-a in vivo. With regard to IL-8, observations obtained by the use of the potent and selective 5-lipoxygenase inhibitor ETH615 points to an intricate cytokine/LT network (141). Th'IS concept is supported by the observation that the anti-inflammatory drug SKFlOS,561 inhibits IL-1, LTB4, and PGH production in vivo and in vitro at comparable doses and concentrations (142), supporting the existence of an interaction between cytokines and eicosanoids in control of the inflammatory reaction. Furthermore, IFN-)Ihas been shown to markedly increase the activity of LTA4-hydrolase, resulting in the formation of LTB4, in a granulocyte-endothelial coculture assay (143). In multiple sclerosis significantly elevated levels of IL-1, TNF-a, and PGE2 are found in stimulated blood M@,while the level of LTB4 is depressed (144). In an in vivo model of IL-1-induced inflammation involving unilateral injection of IL-1 into mouse ears, cyclooxygenase inhibitors were without effect on PMN infiltration, indicating a lack of mediator role for PGs in this response (145). However, inhibition of phospholipase A2 activity by dexamethasone strongly decreases the influx of PMNs, indicating a possible role for 5-lipoxygenase products in IL-1-induced PMN chemotaxis, although it must be considered that GC have other effects on the immune system besides inhibition of phospholipase A*. It has also been suggested that inhibition by GC of IL-2 synthesis by T cells is mediated by suppression of LTB4 formation (111).

It should also be mentioned that the PAF antagonist SRI 63-41, the NSAID flurbiprofen, and prednisolone all partly inhibit IL-1-induced increases in vascular permeability and leukocyte infiltration in the rabbit eye after intravitreal injection of human recombinant IL-la(146). It is concluded that LT, PG, and PAF may act synergistically as mediators of IL-1-induced vascular permeability. There is thus increasing evidence of an interrelationship between eicosanoids, PAF, and cytokines. The regulatory effects of LTB4, PGE2, and PAF on cytokine gene expression has recently been reviewed (147). A complex network of interactions has also been suggested between phagocytic cells and peptide mediators, resulting in oxygen radical-mediated tissue injury. A synergy exists between platelets and PMNs which leads to enhanced oxygen formation by the latter, since IL-1 and TNF-a released from M@ directly stimulate oxygen radical formation in PMNs and prime M 4 for enhanced oxygen radical responses to other agonists (148).

CONCLUSIONS Cytokines are essential mediators of infectious and inflammatory reactions. Most cytokines act locally, but some of the clinically most important cytokines also act systemically as pleiotropic hormones with overlapping and potentially dangerous functions. It is therefore not surprising that cytokines appear to be involved in an ever-increasing number of etiologically and pathogenetically obscure diseases. It is also readily appreciated that several different regulatory mechanisms may have emerged during evolution. Regulation takes place at the cytokine activation stage, during secretion and circulation of the hormones, and at the level of cytokinetarget cell interaction. Hereditary or acquired disturbances in these complex regulatory processes may well contribute to the pathophysiology of many inflammatory diseases, including IBD. As reviewed here, several abnormalities in cytokine release/production have been demonstrated in IBD. At present, however, data providing a direct link between these abnormalities and pathogenic mechanisms are limited. Since biologic response modifiers, including the cytokines themselves, are being increasingly used for therapeutic purposes, and because treatment of many immunoinflammatory disorders is aimed at modifying endogenously produced cytokines, detailed knowledge of the importance of the complex cytokine network in IBD becomes clinically highly relevant. The awareness of the presence of highly specific naturally occurring modulators of immunoinflammatory cytokines and the appearance of more specific therapeutic means of interfering with selective cytokines may also help to improve the management of these immunoinflammatory diseases.

Review

J. BRYNSKOV

0. H. NIELSEN I. AHNFELT-RP)NNE K. BENDTZEN Dept. of Medical Gastroenterology C Herlev Hospital University of Copenhagen Dept. of Pharmacology Leo Pharmaceutical Products

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Ballerup Laboratory of Medical Immunology Dept. of Medicine TTA Rigshospitalet University of Copenhagen Copenhagen, Denmark

REFERENCES 1. Jewell DP, Snook JA. Immunology of ulcerative colitis and Crohn’s disease. In: Allan RN, Keighley MRB, AlexanderWilliams J, Hawkins CF, editors. Inflammatory bowel disease. London: Churchill Livingstone, 1990:127-46. 2. Brynskov J, Freund L, Rasmussen SN, et al. A placebocontrolled, double-blind, randomized trial of cyclosporine therapy in active Crohn’s disease. N. Engl J Med 1989;321:845-50. 3. Brynskov J , Freund L, Rasmussen SN, et al. Final report on a placebo-controlled, double blind, randomised, multicentre trial of cyclosporin treatment in active Crohn’s disease. Scand J Gastroenterol 1991 ;26:68%95. 4. Markowitz J , Daum F. Immunology of inflammatory bowel disease: summary of the proceedings of the subcommittee on immunosuppressive use in IBD. J Pediatr Gastroenterol Nutr 1991;12:411-23. 5. Bentzen K. Cellular and molecular processes underlying immunoinflammation. In: Matsson P, Ahlstedt S, Venge P, Thorell J , editors Clinical impact of the monitoring of allergic inflammation. London: Academic Press, 1991:187-200. 6. Bendtzen K. Immune hormones (cytokines); pathogenic role in autoimmune rheumatic diseases and endocrine diseases. Autoimmunity 1989;2:177-89. 7. Miura M, Hiwatshi N. Cytokine production in inflammatory bowel disease. J Clin Lab Immunol 1985;33:232-44. 8. Satsangi J, Wolstencroft RA, Cason J , Ainley CC, Dumonde DC, Thompson RPH. Interleukin 1 in Crohn’s disease. Clin Exp Immunol 1987;67:594-605. 9. Suzuki Y, Quinn DG, Tobin A, Whelan CA, O’Morain C. Production of interleukin 1 by highly purified monocytes in inflammatory bowel disease. Eur J Gastroenterol Hepatol 1991;3:45-9. 10. Hodgson HJF, Mazlam MZ. Cytokines-are they different in ulcerative colitis and Crohn’s disease. In: Goebell H, Malchow H, Ewe K, Koelbel C, editors. Inflammatory bowel disease. Progress in basic research and clinical implications. Dordrecht: Kluwer Academic Publishers, 1991:161-8. 11. Mahida YR, Wu K, Jewell DP. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis or Crohn’s disease. Gut 1989;30:835-8. 12. Brynskov J , Tvede N, Vilien M, Andersen CB, Bentzen K. Increased concentrations of interleukin lp, interleukin 2, and soluble interleukin-2 receptors in endoscopical mucosal biopsy specimens with active inflammatory bowel disease. Gut 1992;33:55-8.

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13. Ligumski M, Simon PL, Karmeli F, Rachmilewitz D. Role of interleukin 1 in inflammatory bowel disease: enhanced production during active disease. Gut 1990;31:6869. 14. Rachmilewitz D, Simon PL, Schwartz LW, Griswald DE, Fondacaro JD, Wasserman MA. Inflammatory mediators of experimental colitis in rats. Gatroenterology 1989;97:32637. 15. Radema SA, vanDeventer SJH, Cerami A. Interleukin 18 is expressed predominantly by enterocytes in experimental colitis. Gastroenterology 1991;100:118&8. 16. Brynskov J , Hansen MB, Reimert C, Bentzen K. Inhibitor of interleukin 1LY and interleukin lp-induced T-cell activation in serum of patients with active Crohn’s disease. Dig Dis Sci 1991;36:737-42. 17. Larrick JW. Native interleukin 1 inhibitors. Immunol Today 1989;10:61-66. 18. Bendtzen K, Svenson M, Jmsson V, Hippe E. Autoantibodies to cytokines-friends or foes? Immunol Today 1990;11:167-9. 19. Cannon JG, Dinarello CA. Increased plasma interleukin 1 activity in women after ovulation. Science 1985;227:1247-9. 20. Dinarello CA, Rosenwasser LJ, Wolf SM. Demonstration of a circulating suppressor factor of thymocyte proliferation during endotoxin fever in humans. J Immunol 1981;127:2517-19. 21. Liao Z, Grimshaw RS, Rosenstreich DL. Identification of a specific interleukin 1 inhibitor in the urine of febrile patients. J Exp Med 1984;159:12636. 22. Seckinger P, Williamson K, Balavoine JF, et al. A urine inhibitor of interleukin 1activity affects both interleukin l a a n d lpbut not tumour necrosis factor. J Immunol1987;139:1541-5. 23. Seckinger P, Lowenthal JW, Williamson K, Dayer JM, MacDonald HR. A urine inhibitor of interleukin 1 activity that blocks ligand binding. J Immunol 1987;139:15469. 24. Arend WP. Interleukin 1receptor antagonists. A new member of the interleukin 1 family. J Clin Invest 1991;88:144>51. 25. Dinarello CA, Thompson RC. Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today 1991;12:404-10. 26. Eisenberg SP, Brewer MT, Verderber E, Heimdal P, Brandhuber BJ, Thompson RC. Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism. Proc Natl Acad Sci 1991;88:52326. 27. Bendtzen K, Mandrup-Poulsen T, Nerup J , Nielsen JH, Dinarello CA, Svenson M. Human PI 7 interleukin 1 is cytotoxic for pancreatic islets of Langerhans. Science 1986;232:15457. 28. Onozaki K, Matsushima K, Aggarwal BB, Oppenheim JJ. Human interleukin 1 is cytocidal factor for several tumor cell lines. J Immunol 1985;135:3962-8. 29. Pettipher ER, Henderson B, Higgs GA, Moncada S. Arthritogenic activity of interleukin 1 in leucopaenic rabbits. Congress of the International Association for Biological StandardsCytokines;l987; London, England. 30. Deem RL, Shananan F, Targan SR. Triggered human mucosal T cells release tumor necrosis factor-alpha and interferongamma which kill human colonic epithelial cells. Clin Exp Immunol 1991;83:79-84. 31. Cantrell DA, Smith KA. The interleukin-2 T-cell system. Science 1984;224:1312-6. 32. Ruscetti FW, Gallo RC. Human T lymphocyte growth factor: regulation of growth and function of T lymphocytes. Blood 1981;57:379-94. 33. Ebert EC, Wright SC, Lipshutz WH, Haupman SP. T cell abnormalities in inflammatory bowel diseases are mediated by interleukin 2. Clin Immunol Immunopathol 1984;33:232-44. 34. Fiocchi C. Lymphokines and the intestinal immune response. Role in inflammatory bowel disease. Immunol Invest 1989; 18:91-102. 35. Kusugami K, Matsuura T, West GA, Youngman KR, Rachmilewitz D, Fiocchi C. Loss of interleukin-2-producing intestinal CD4+ T cells in inflammatory bowel disease. Gastroenterology 1991;101:1594-1605. 36. Fiocchi C, Hilfiker ML, Youngman KR, Doerder NC, Finke JH. Interleukin 2 activity of human intestinal mucosa mono-

Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 02/06/15 For personal use only.

904

Review

nuclear cells. Decreased levels in inflammatory bowel disease. Gastroenterology 1984;86:73442. 37. Fiocchi C, Tubbs R, Youngman KR. Human intestinal mucosal mononuclear cells exhibit lymphokine-activated killer cell activity. Gastroenterology 1985;88:625-37. 38. Manzano L, Alvarez-Mon M, Abreu L, et al. Functional impairment of natural killer cells in active ulcerative colitis: revision of the defective natural killer activity by interleukin 2. Gut 1992;33:24651. 39. James SP. Remission of Crohn’s disease after human immunodeficiency virus infection. Gastroenterology 1988;96:16679. 40. Miyasaka N , Nakarama T, Russell IJ, Tala1 N . Interleukin 2 deficiencies in rheumatoid arthritis and systemic lupus erythematosus. Clin Immunol Immunopathol 1984;31:109-17. 41. Davidsen B. Concanavalin A induced suppressor activity exerted by peripheral blood mononuclear cells-with special reference to chronic inflammatory bowel disease. Dan Med Bull 1988;35:201-22. 42. Selby WS, Janossy G , Bonfill M, Jewell DP. Intestinal lymphocyte subpopulation in inflammatory bowel disease: An analysis by immunohistological and cell isolation techniques. Gut 1984;25:32-40. 43. James SP, Fiocchi C, Graeff AS, Strober W. lmmunoregulatory functions of lamina propria T in Crohn’s disease. Gastroenterology 1985;88:1143-50. 44. Cornaby A , Simpson MA, Vannrice R. Dempsey RA, Madras PN, Monaco AP. Interleukin-2 production in plasma and urine, plasma interleukin-2 receptor levels, and urine cytology as a means of monitoring renal allograft recipients. Transplant Proc 1988;20 Suppl 1:108-10. 45. Sunder-Plassmann G , Stockenhuber F, Balcke 0 . Serum interleukin 2 activity in renal graft recipients. Transplant Proc 1988;20:387-9. 46. Trotter JL, Clifford DB, Anderson CB, van der Veen RC, Hicks BC, Banks G. Elevated serum interleukin-2 levels in chronic progressive multiple sclerosis. N Engl J Med 1988; 322: 1206. 47. Wolf RE, Baethge BA. lnterleukin-la, interleukin-2, and soluble interleukin-2 receptors in polymyositis. Arthritis Rheum 1990;33: lOO7-14. 48. Brynskov J, Tvede N. Plasma interleukin-2 and a soluble/ shed interleukin-2 receptor in serum of patients with Crohn’s disease. Effect of cyclosporin. Gut 1990;31:795-9. 49. James SP, Mullin GE. Lymphokine production by mucosal T cells in inflammatory bowel disease. In: Goebell H , Ewe K, Malchow H , Koeibel CH, editors. Inflammatory bowel disease. Progress in basic research and clinical implication. Dordrecht: Kluwer Academic Publishers, 1991:71-81. 50. Fujii M, Sogamura K, Sabno K, Nakai M, Sugita K, Hinuma Y. High-affinity receptor-mediated internalization and degradation of interleukin 2 in human T-cells. J Exp Med 1986; 163:55&62. 51. Sharon M, Klausner RD, Cullen BR, Chizzonite R, Leonard WJ. Novel interleukin-2 receptor subunit detected by crosslinking under high-affinity conditions. Science 1986;23: 859-63. 52. Teshigawara K, Wang H, Kato K, Smith KA. Interleukin 2 high-affinity receptor expression requires two distinct binding proteins. J Exp Med 1986;165:223-38, 53. Tsudo M. Kozak RW, Goldman CK, Waldman TA. Demonstration of a non-Tac peptide that binds interleukin 2: a potential participant in multichain interleukin 2 receptor complex. Proc Natl Acad Sci 1986;83:9694-8. 54. Forsythe JL, Shenton BK, Parrot NR, Taylor RM, Proud G . Plasma interleukin 2 receptor levels in renal allograft dysfunction. Transplantation 1989;48:155-7. 55. A d a m DH, Hubscher SG, Wang L, Elisa E . Soluble interleukin-2 receptors in serum and bile of liver transplant recipients. Lancet 1989;1:469-71. 56. Marcon L, Fritz ME, Kurman CC, Jensen JC, Nelson DL. Soluble Tac peptide is present in the urine of normal individuals

and at elevated levels in patients with adult T cell leukaemia (ATL). Clin Exp Immunol 1988;73:29-33. 57. Lobo-Yeo A, Mieli-Verganis G , Mowat AP, Verganis D . Soluble interleukin 2 receptors in autoimmune chronic active hepatitis. Gut 1990;31:690-3. 58. Wolf RE, Brelsford WG. Soluble interleukin-2 receptors in systemic lupus erythematosus. Arthritis Rheum 1988;31:72935. 59. Crabtree JE, Juby LD, Heatley RV, Lobo AJ, Bullimore DW, Axon ATR. Soluble interleukin-2 receptor in Crohn’s disease: relation of serum concentrations to disease activity. Gut 1990;31:1033-6. 60. Mahida YR, Gallagher A, Kurlac L, Hawkey CJ. Circulating and tissue interleukin 2 receptor levels in inflammatory bowel disease. Clin Exp Immunol 1990;82:75-80. 61. Mueller C , Knoflach P, Zielinski CC. T-cell activation in Crohn’s disease. Increased levels of soluble interleukin 2 receptor in serum and in supernatants of stimulated peripheral blood mononuclear cells. Gastroenterology 1990;98:639-46. 62. Mahida YR, Patel S, Wu K, Jewell DP. Interleukin-2 receptor expression by macrophages in inflammatory bowel disease. Clin Exp Immunol 1988;74:382-6. 63. Pallone F, Fais S, Squarcia 0,Biancone L, Pozzilli P, Biorivant M. Activation of peripheral blood and intestinal lamina propria lymphocytes in Crohn’s disease. Gut 1990;28:745-53. 64. Raedler A , Schreiber S. Immunology of ulcerative colitis. Hepatogastroentcrology 1989;36:213-8. 65. Malizia G , Calabrese A, Cottone M, et al. Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease. Gastroenterology 1991; 100:15&9. 66. Waldmann TA, Goldman CK, Robb RJ, et al. Expression of interleukin-2 receptors in activated B cells. J Exp Med 1984;160:145C-66. 67. Schreiber S, Raedler A, Conn AR, Rombeau JL, MacDermott RP. Increased in vitro release of soluble interleukin 2 receptors by colonic lamina propria mononuclear cells in inflammatory bowel disease. Gut 1992;33:23644. 68. Rubin LA, Jay G, Nelson DL. The released interleukin 2 receptor binds interleukin 2 efficiently. J Immunol 1986; 137~3841-4. 69. Bendtzen K. Clinical significance of cytokines. Natural and therapeutic regulation. Sem Clin Immunol 1991;3:5-13. 70. Snick J. Interleukin-6: an overview. Ann Rev Immunol I990;U :253-78. 71. Andus T, Gross V, Casar I, et al. Activation of monocytes during inflammatory bowel disease. Pathobiology 1991;59: 1 6 6 70. 7 2 . Mitsuyama K, Sata M, Tanikawa K. Significance of interleukin6 in patients with inflammatory bowel disease. Gastroenterol Jpn 1991;26:2&8. 73. Suzuki Y, Saito H, Kasanuki J , Kishimoto T, Tamura Y, Yoshida S. Significant increase of interleukin 6-production in blood mononuclear leukocytes obtained from patients with active inflammatory bowel disease. Life Sci 1990;47:2193-7. 74. Mahida YR, Kurlac L, Gallagher A, Hawkey CJ. High circulating concentrations of interleukin-6 in active Crohn’s disease but not ulcerative colitis. Gut 1991;32:1531-4. 75. Gross V, AndusT, Caesar J, Roth M, Scholmerich J. Evidence for continuous stimulation of interleukin-6 production in Crohn’s disease. Gastroenterology 1992;102:514-9. 76. Nielsen OH. In vitro studies on the significance of arachidonate metabolism and other oxidative processes in the inflammatory response of human neutrophils and macrophages with special reference to chronic inflammatory bowel disease. Scand J Gastroenterol 1988;23 Suppl 150:1-21. 77. Sherry B, Cerami A. Small cytokine superfamily. Cur Opin lmmunol 1991;3:5660. 78. Matsushima K, Morishita K, Yoshimura T, et al. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med 1988; 167:1883-93.

Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 02/06/15 For personal use only.

Review 79. Oppenheim JJ, Zachariae COC, Mukaida N, Matsushima K. Properties of the novel proinflammatory supergene ‘intercrine’ cytokine family. Ann Rev Immunol 1991;9:617-48. 80. Mahida YR, Ceska M, Lindley I, Hawkey CJ. Increased mucosal interleukin 8 (NAP-1) in active ulcerative colitis [abstract]. Gastroenterology 1991;100:A595. 81. Djeu JY, Matsushima K, Oppenheim JJ, Shiotsuki K, Blanchard DK. Functional activation of human neutrophils by recombinant monocyte-derived neutrophil chemotactic factor/ IL-8. J Immunol 1990;144:2205-10. 82. Matsushima K, Oppenheim JJ. Interleukin 8 and M C A F novel inflammatory cytokines inducible by IL 1 and TNF. Cytokine 1989;1:2-13. 83. Schroeder JM. The monocyte-derived neutrophil activating peptide (NAP-l/interleukin 8) stimulates human neutrophil arachidonate-5-lipoxygenase, but not the release of cellular arachidonate. J Exp Med 1989;170:847-63. 84. Thelen M, Peveri P, Kernen P, von Tscharner V, Wlaz A, Baggiolini M. Mechanism of neutrophil activation by NAF, a novel monocyte-derived peptide agonist. FASEB J 1988;2: 27026. 85. Dunham I, Sargent CA, Trowsdale J , Cambell RD. Molecular mapping of the human major histocompatibility complex by pulsed-field gel electrophoresis. Proc Natl Acad Sci 1987;84: 7237-4 1. 86. Ragoussis I, Bloemer K, Weiss EH, Ziegler A. Localization of the genes for tumor necrosis factor and lymphotoxih between the HLA class I and 111 regions by field inversion gel electrophoresis. Immunogenetics 1988;27:66-9. 87. Bendtzen K, Morling N, Fomsgaard A, et al. Association between HLA-D2R and production of tumor necrosis factor a and interleukin 1 by mononuclear cells activated by pipopolysaccharide. Scand J Immunol 1988;28:599-606. 88. Fugger L, Bendtzen K, Morling N, Ryder L, Svejgaard A. Possible correlation of TNFa-production with RFLP in humans. Eur J Haematol 1989;43:255-6. 89. Jacob CO, Lewis GD, McDevitt HO. MHC class 11-associated variation in the production of tumor necrosis factor in mice and humans: relevance to the pathogenesis of autoimmune disease. Immunol Res 1991;lO:15668. 90. Ellis A, McKay J, Woodrow JC, McConnell RB. Tissue antigens and inflammatory bowel disease. Front Gastroent Res 1986;11:35-41. 91. Beutler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med 1987;316:379-85. 92. Bendtzen K. Why is too little TNF bad? Cytokine 1991;3:6367. 93. Hyams JS, Treem WR, Eddy E, Wyzga N, Moore RE. Tumor necrosis factor-&is not elevated in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1991;12:23>6. 94. Murch SH, Lamkin VA, Savage MO, Walker-Smith JA, MacDonald ‘IT. Serum concentrations of tumor necrosis factor a in childhood chronic inflammatory bowel disease. Gut 1991; 32:913-7. 95. Braegger CP, Nicholls S , Murch SH, Stephens S, MacDonald ‘IT.Tumor necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 1992;339:89-91. 96. Fais S, Capobianchi MR, Pallone F, et al. Spontaneous release of interferon y by intestinal lamina propria lymphocytes in Crohn’s disease. Kinetics of in vitro response to interferon y inducers. Gut 1991;32:403-7 97. MacDonald TT, Hutchings P, Choy M-Y, Murch S, Cooke A. Tumor necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol 1990-81:301-5. 98. Lieberman BY, Fiocchi C, Youngman KR, Sapatnekar WK, Proffitt MR. Interferon y production by human intestinal mucosal cells: decreased levels in inflammatory bowel disease. Dig Dis Sci 1988;33:1297-1304. 99. Fiocchi C. Lymphokines and the intestinal immune response. Role in inflammatory bowel disease. Immunol Invest 1989;18:91-102. 100.Mahida YR, Lamming CED, Gallagher A, Hawthorne AB,

905

Hawkey CJ. 5-aminosalicylic acid is a potent inhibitor of interleukin 18 production in organ culture of colonic biopsy specimens from patients with inflammatory bowel disease. Gut 1991;32:5O-4. 101. Remvig L, Anderson B. Salicylazosulfapyridine effect on endotoxin-induced production of interleukin-1-like factor from human monocytes in vitro. Scand J Rheumatol 1990;19:114. 102. Fujiwara M, Mitsui K, Yamamoto I. Inhibition of proliferative responses and interleukin 2 productions by salazosulfapyridine and its metabolites. Jpn J Pharmacol 1990;54:121-31. 103. Shanahan F, Niederlehner A, Carramanzana N, Anton P. Sulfasalazine inhibits the binding of TNFa to its receptor. Immunopharmacology 1990;20:217-24. 104. Cominelli F, Zipser RD, Dinarello CA. Sulfasalazine inhibits cytokine production in human mononuclear cells: a novel antiinflammatory mechanism. Gastroenterology 1988;96:A96. 105. Beato M, Briiggemeier U, Chalepakis G, et al. Regulation of transcription by glucucorticoids. In: Cohen P, Foulkes JG, editors. The hormonal control of gene transcription. Amsterdam: Elsevier Science Publishers B.V., 1991:117-28. 106. DiRosa M, Flower RJ, Hirata F, Parente L, Russo-Marie F. Antiphospholipase proteins. Prostaglandins 1984;28:441-2. 107. Werb Z, Foley R, Munck A. Interation of glucocorticoids with macrophages. Identification of glucocorticoid receptors in monocytes and macrophages. J Exp Med 1978;147:1684-93. 108. Bendtzen K, Petersen J. Effects of cyclosporin A (CyA) and methylprednisolone (MP) on the immune response. 1. T cellactivating factor (IL-1) abrogates CyA- but not MP-induced suppression of antigen-induced lymphokine production. Immuno1 Lett 1982;5:79-83. 109. Lew W, Oppenheim JJ, Matsushima K. Analysis of the suppression of IL-la and IL-18 production in human peripheral blood mononuclear adherent cells by a glucocorticoid hormone. J Immunol 1988;140:1895-2. 110. Horst HJ, Flad HD. Corticosteroid-interleukin 2 interactions: inhibition of binding of interleukin 2 to interleukin 2 receptors. Clin Exp Immunol 1987;68:151-61. 111. Goodwin JS, Atluru D, Sierakowski S, Lianos E A . Mechanism of action of glucocorticoids. Inhibition of T cell proliferation and interleukin 2 production of hydrocortisone is reversed by leukotriene Bq.J Clin Invest 1986;77:1244-50. 112. Arya SK, Wong-Staal F, Gallo RC. Dexamethasone-mediated inhibition of human T cell growth factor and gamma interferon messenger RNA. J Immunol 1984;133:273-6. 13. Mokoena T, Gordon S. Human macrophage activation. Modulation of mannosyl, fucosyl receptor activity in vitro by lymphokines, gamma and alpha interferons, and dexamethasone. J Clin Invest 1985;75:624-31. 14. Culpepper JA, Lee F. Regulation of IL-3 expression by glucocorticoids in cloned murine T lymphocytes. J Immunol 1985;135:3191-7. 15. Wallen N, Kita H , Weiler D, Gleich GJ. Glucocorticoids inhibit cytokine-mediated eosinophil survival. J Immunol I991 ;147:349@5. 16. Andus T, Gross V, Casar I, Krumm D, Hosp J , David M, Scholmerich J . Activation of monocytes during inflammatory bowel disease. Pathobiology 1991;59:16670. 17. Mukaida N, Shiro M, Matsushima K. Genomic structure of the human monocyte-derived neutrophil chemotactic factor interleukin 8. J Immunol 1989;143:1366-71. 18. Harding MW, Galat A, Uehling DE, Schreiber SL. A receptor for the immunosuppressant FK.506 is a cis-trans peptidyi-prolyl isomerase. Nature 1989;341:758-60. 119. Siekierka JJ, Hung SHY, Poe M. Lin CS, Sigal NJ. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 1989;341:755-7. 120. Elliot JF, Lin Y , Mizel SB, Bleackley RC, Harnish DG, Laetkau V. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science 1984:226:143941. 121. Bunjes D, Hardt C, Rollinghoff M, Wagner H . Cyclosporin A mediates immunosuppression of primary cytotoxic T cell

Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 02/06/15 For personal use only.

906

Review

responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol 1981;11:657-61. 122. Kalman VK, Klimpel GR. Cyclosporin A inhibits the production of yinterferon, but does not inhibit production of virus induced IFN a/@.Cell Immunol 1983;78:122-9. 123. Wasik MA, Beller DI. Induction of macrophage membrane interleukin 1 expression by T-cell dependent and T-cell independent pathways is inhibited by cyclosporin A. Clin Immunol Immunopathol 1989;52:331-40. 124. Kupiec-Weglinski JW, Filho MA, Strom TB, Tihey BL. Sparing of suppressor cells: a critical action of cyclosporine. Transplantation 1984;38:97-101. 125. Evans CM, Philips AD, Walker-Smith JA, MacDonald TT. Activation of lamina propria T cells induces crypt epithelial proliferation and goblet cell depletion in cultured human fetal colon. Gut 1992;33:230-5. 126. Hess AD, Colombani PM. Cyclosporin A . Mechanism of action (in vitro studies). Progr Allergy 1986;38:198-221. 127. Knudsen PJ, Dinarello CA, Strom TB. Prostaglandins posttranscriptionally inhibit monocyte expression of interleukin- 1 activity by increasing intracellular cyclic adenosine monophosphate. J Immunol 1986;137:3189-94. 128. Monick M, Glazier J, Hunninghake GW. Human alveolar macrophages suppress interleukin-1 (IL-1) activity via the secretion of prostaglandin E2. Am Rev Respir Dis 1987;135:727. 129. Sat0 IY, Kobayashi K, Yamagata N, et al. Modulation of granuloma formation in vitro by endogenous mediators. Immunopharmacol 1991;21:73-82. 130. Haynes DR, Wright PF, Whitehouse MW, Vernon-Roberts B. The cyclo-oxygenase inhibitor, piroxicam, enhances cytokineinduced lymphocyte proliferation in vitro and in vivo. Immunol Cell Biol 1990;68:225-30 131. DinarelloCA. Interleukin-1 and other growth factors. In: Kelly WN, Harris ED, Ruddy S, Sledge CB, editors. Textbook of rheumatology. Philadelphia: W. B. Saunders Company, 1989: 285-99. 132. Baker PE, Fahey JV, Munck A. Prostaglandin inhibition of T cell proliferation is mediated at two levels. Cell Immunol 1981;61:52-61. 133. Rappaport RH, Dodge DR. Prostaglandin E inhibits the production of human interleukin 2. J Exp Med 1982;155:943-8. 134. Browning JL, Ribolini A. Interferon blocks interleukin 1induced prostaglandin release from human peripheral monocytes. J Immunol 1987;138:2857-63. 135. Hart PH, Vitti GF, Burgess DR, Whitty GA, Piccoli DS,

Hamilton JA. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin-1 a,d prostaglandin E2. Proc Natl Acad Sci 1989;86:3803-7. 136. Henderson B, Pettipher ER. Comparison of the in vivo inflammatory activities after intra-articular injection of natural and recombinent IL-1 alpha and IL-1 beta in the rabbit. Biochem Pharmacol 1988;37:4171-6. 137. Hellerstein MK, Meydani SN, Meydani M, Wu K, Dinarello CA. Interleukin-1-induced anorexia in the rat. Influence of prostaglandins. J Clin Invest 1989;84:228-35. 138. Boraschi D, Villa L, Volpini G , Bossu P, Censini S, Ghiara P. Differential activity of interleukin 1 alpha and interleukin 1 beta in the stimulation of the immune response in vivo. Eur J Immunol 1990;20:317-21. 139. Hauptmann B, VanDamme J, Dayer JM. Modulation of IL-1 inflammatory and immunornodulatory properties by IL-6. Eur Cytokine Netw 1991;2:3946. 140. Ferrandiz MI, Foster SJ. Tumour necrosis factor production in a rat airpouch model of inflammation: role of eicosanoids. Agents Actions 1991;32:28994. 141. Kirstein D , Thomsen MK, Ahnfelt-Rbnne I. Inhibition of leukotriene biosynthesis and polymorphonuclear leukocyte functions by orally active quinolylmethoxyphenylamines.Pharmacol Toxicol 1991;68:125-30. 142. Marshall PJ, Griswold DE, Breton J , Webb EF, Hillegas LM, Sarau HM. Pharmacology of the pyrroloimidazole, SF & F 105809. I. Inhibition of inflammatory cytokine production and of 5-lipoxygenase and cyclooxygenase-mediated metabolism of arachidonic acid. Biochem Pharmacol 1991;42:81>24. 143. Rekonen R, Ustinov J. Interferon-gamma augments hydrolysis of LTA4 to LTB4 by endothelial cells. Prostaglandins 1990; 39 1205-1 1. 144. Merrill JP, Strom SR, Ellison GW, Myers LW. In vitro study of mediators of inflammation in multiple sclerosis. J Clin Immunol 1989;9:84-96, 145. Maloff BL, Shaw JE, Di-Meo TM. IL-1 dependent model of inflammation mediated by neutrophils. J Pharmacol Meth 1989;22:133-40. 146. Rubin RM, Rosenbaum JT. A platelet-activating factor antagonist inhibits interleukin 1-induced inflammation. Biochem Biophys Res Commun 1988;154:429-36. 147. Rola-Pleszczynski M, Stankova J. Cytokine gene regulation by PGE2, LTB, and PAF. Med Inflam 1992;1:5-8. 148. Ward PA, Warren JS, Johnson KJ. Oxygen radicals, inflammation, and tissue injury. Free Radic Biol Med 1988;5:403-8.