Scand J Gastroenterol 1992;27:897-906.


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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-



Table I. Clinically important human inflammatory cytokines Acronym


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



T cells



T cells



T cells



T cells



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



Monocytes/macrophages T cells Keratinocytes



T cells


IFN-al/-Cu2 (>20 subtypes)



IFN-/3 (=IFN-P,)

Many cells (virus-infected)


T cells





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


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$J, and NK cells (62) also express IL-2R. MMC from patients with CD, but not UC, secrete spontaneously increased amounts of sIL-2R in vitro and have been proposed to account for the increased serum values (67). The precise function of sIL-2R is also not known. SIL-2R binds IL-2 and has therefore been proposed to play a role as a downregulator of T-cell functions (68). This proposal appears rather unlikely, however, considering the very low affinity of sIL-2R to its natural ligand (69). IL-6 IL-la, IL-lP, and TNF are all potent inducers of IL-6 in both [email protected] and T cells (69). IL-6 may act as an important second messenger of IL-1 and TNF. IL-6 plays a key role in the acute-phase response by inducing increased acute-phase protein synthesis in hepatocytes (6). Furthermore, IL-6 stimulates T and B cells, most likely because it increases the responsiveness of these cells to IL-2 (70). Several studies have dealt with IL-6 in IBD (71-75). However, elevated serum and mucosal levels have been reported (72,73,75). Although serum concentrations of IL6 do not correlate with clinical activity in CD, they correlate, as expected, with acute-phase protein levels. Because of the short half-life of IL-6 (5 min), the increased serum values have been proposed to reflect a continuous stimulation of IL-6-producing cells (754, probably M$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 [email protected] (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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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 [email protected] 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 [email protected],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 [email protected] 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.



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

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Cytokines in inflammatory bowel disease.

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