PHYSIOLOGICAL REVIEWS Vol. 70, No. 2, April 1990
Printed
in U.S.A.
Cytokines and Endothelial JORDAN Departments
of Pathology,
Brigham
S. POBER
and Wmen
AND RAMZI
‘s Hospital
Cell Biology S. COTRAN
and Harvard
Medical
I. Introduction ............................................................................... II. Specific Cytokine Actions on Endothelial Cells ................................................ A. Interleukinl ............................................................................ ................................................... B. Tumor necrosis factor and lymphotoxin C. Interferons ............................................................................. .................................................. D. Other cytokines with endothelial actions ................................... III. Cytokine Actions on Endothelium in Pathological Processes A. Acuteinflammation ..................................................................... B. Shwartzmanreaction .................................................................... ................................................................. C. Delayed hypersensitivity D. Normallymphocyterecirculation ......................................................... E. Vascular leakage ........................................................................ ....................................................... F. Autoimmunity and vascular injury G. Transplantation ......................................................................... H. Angiogenesis ............................................................................ IV. Conclusions ................................................................................
I. INTRODUCTION
The effector phase of an immune response involves the secretion of protein mediators by antigen-stimulated T lymphocytes, which serve to recruit and activate the various responsive cell populations that comprise the inflammatory infiltrate. Some of these responsive cell populations, most notably mononuclear phagocytes, in turn secrete additional protein mediators that influence the reaction. These lymphocyte-derived and mononuclear phagocyte-derived mediators were called “lymphokines” and “monokines,” respectively. When it was discovered that cells not traditionally part of the immune system could also secrete similar or identical protein mediators, these molecules were collectively renamed as “cytokines” (55). Although there is no universally accepted rigorous definition of a cytokine, to be considered to be a cytokine a protein I) must mediate some aspect of inflammation and 2) must be elicited as part of the immune response to antigen. This definition does not exclude the possibility of secretion in response to other stimuli, and, in fact, for mononuclear phagocyte-derived mediators, microorganisms and their products (e.g., endotoxins) may be far more potent stimulators than antigen-generated signals. Cytokines are not always secreted; in some cases they may be expressed on the cell surface of the stimulated cell. However, whether secreted or surface expressed, cytokines share a common mode of action: they bind to specific protein receptors on the surface of their target cell. Cytokines have no enzymatic activities or chemical reactivities but indirectly function through altering the 0031-9333/90
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behavior of a target cell. In this sense, cytokines are similar to hormones. The target cell for cytokines may be the cell of origin (autocrine actions), nearby cells (paracrine actions), or, as for true hormones, distant target cells in other organs, such as liver or brain (endocrine actions). There are two other general features of cytokine function. First, one cytokine often causes the secretion of a second cytokine by its target cell and so on. This phenomenon has been described as a cytokine cascade. Second, individual cytokines often modulate the actions of other cytokines on the same target cell. Such interactions may be mutually inhibitory, additive, synergistic, or even result in novel effects not seen with either individual cytokine. Thus the precise biological effect of a cytokine will be determined by the milieu in which it acts. Many of the early studies on cytokines were performed in vitro using leukocytes isolated from blood or lymphoid organs. This led to the conclusion that the principal targets of cytokine actions were leukocytes. At one point, the narrow view that cytokines were leukocyte-derived mediators that act on other leukocytes gave rise to the alternative name of “interleukins” for these molecules and the assignment of numbers within the so-called family of interleukins to distinguish among the different mediators (e.g., interleukin 1, interleukin 2) (1). It is now apparent that tissue cells other than leukocytes are important targets of cytokines and, in some instances, may be the major targets. Among the tissue cells it is now appreciated that the endothelial lining of blood vessels is a critical focus of many cytokine actions. In retrospect, this is not sur427
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prising. Endothelium is the gatekeeper of the tissues from the perspective of the bloodstream, and alterations of the endothelium are important determinants in regulating traffic of circulating cells and molecules into the tissues (for review see Ref. 59). The gatekeeping function of endothelium has especially focused attention on the microvasculature and particularly on the postcapillary venular segments where leukocyte trafficking and macromolecular extravasation are known to occur (174). In general, there are three separate responses of microvascular endothelium in vivo that may be cytokine related. First, endothelial cells may be injured during immune responses. For example, the rejection of transplanted organs appears primarily to be an immune response against foreign endothelial cells (182). In this context, it is possible that endothelial injury may result directly from cytokine binding to endothelial cell receptors. In the case of endothelium, injury may manifest as frank denudation, focal cell necrosis, or more subtle loss of integrity, resulting in varying degrees of “dysfunction” (105). Second, endothelial cells may migrate, proliferate, and form new blood vessels (88, 89). The formation of new blood vessels by outgrowth of existing vessels, called angiogenesis, is a key component of the tissue remodeling that accompanies chronic inflammation, and there is considerable recent evidence that certain cytokines can initiate angiogenesis (i.e., act as angiogenic factors). Third, endothelial cells may acquire the capacity to perform new functions without evidence of cell injury or cell division. This process, which we have called activation, is the result of quantitative changes in certain gene products and most certainly is a response to cytokines (61, 217). Because activation is defined by altered capacities and functions, it follows that there may be numerous distinct (but potentially overlapping) states of activation. Moreover, the distinction between activation and proliferation may be artificial and is certainly not exclusive; indeed, the distinctions between growth factors and cytokines are quite arbitrary and difficult to define. Finally, although a clear cut distinction exists between injury and activation, the functions displayed by an activated endothelial cell may well lead to endothelial injury through indirect mechanisms (see sect. III). The last topic we consider is how endothelial cell responses to cytokines may be studied. Endothelial cell cultures (102, 130) have been an invaluable tool in defining the responses to cytokines, and much of the work we review here is based on such experiments. A cell culture system is infinitely simpler than in vivo settings and thus much more amenable to analysis. However, the types of large vessel and microvascular endothelial cells in culture do not necessarily share the characteristics of the particular type of endothelial cell of greatest interest, i.e., the postcapillary venular endothelium. Moreover, there may well be organ-specific differences among endothelial cells that are retained by cultured cells. Therefore umbilical vein-derived or adipose-derived endothelium may be a poor model for renal or
RAMZI
S. COTRAN
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brain endothelium. Of even greater concern is that particular differentiated features of endothelial cell behavior may be lost on isolation for cell culture or overwhelmed by the conditions and factors needed to propagate cultured cells. In short, it is always necessary to ask whether a particular effect observed in a particular culture system is an accurate model of the in vivo response observed in the venules of the vascular bed of interest. For these reasons, experimental animal models to study cytokine effects have been developed, and attempts to document some of these effects in human pathological conditions have been conducted. We have found that immunocytochemical demonstration of activation antigens, applied to organ culture systems and to tissue biopsies, is an invaluable tool for making such connections. II.
SPECIFIC
CYTOKINE
ACTIONS
ON ENDOTHELIAL
CELLS
In this section we review the specific actions of a number of cytokines on endothelial cells in vitro and, where known, in vivo. We consider both the actions of individual cytokines and of cytokines in combination. Published observations as well as unpublished data from the authors’ laboratories are discussed. In section III, we synthesize these observations by considering a number of pathological processes in which cytokinemediated responses of endothelium may be of particular import. A. Interleukin
I
Interleukin 1 (IL-l) is a pleiotropic inflammatory mediator, with numerous biological effects on many different cell types (209, 210). It is therefore not surprising that it has been repeatedly rediscovered in a variety of different contexts. The first described activity of IL-1 was as a costimulator of T lymphocytes (100). The standard bioassay for IL-1 is synergistic stimulation of murine thymocyte proliferation when combined with a mitogenic plant lectin, such as concanavalin A or phytohemagglutinin. Because endotoxin may exert similar effects, an endotoxin-resistant mouse strain (e.g., CSH-HEJ) is conveniently selected as the source of thymocytes. An alternative bioassay is to use costimulation of certain murine T-cell clones, such as DlO.G4.1, which have greater specificity and sensitivity for IL-1 than thymocytes (144). The most readily available source of biological IL-1 is conditioned medium of mononuclear phagocytes exposed for 12-24 h to bacteria or endotoxin. Mononuclear phagocyte-derived IL-1 consists of two major polypeptides, each of -17 kDa, with isoelectric points of near neutrality (the predominant species) and near pH 5.0 (the lesser species) (173). There are at least two distinct genes, the products of which have IL-1 bioactivity. Interleukin la, the first one cloned in mouse (168), encodes for the ~15.0 species (44), and IL-l& the
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first one cloned in human (13), encodes for the p1 7.0 species (45). There is only limited homology between the amino acid sequences of IL-la and IL-l& Both IL-1 genes actually encode for primary translation products of ~33-34 kDa; the mature IL-l species are derived from the carboxy-terminal halves of the putative precursors (44,45). The 33-kDa species of IL-la is biologically active, whereas IL-lp only gains activity when the amino-terminal half is removed (173). Neither IL-1 gene product contains any membrane-spanning sequence or putative leader sequence typically involved in secretion. In some cases, IL-l bioactivity is retained in association with the cell of origin, can be assayed on intact (or even fixed intact) cells, and can be isolated with the plasma membrane of subfractionated cells (148). Such “membrane IL-l” appears to consist exclusively of IL-la (58, 149). There are no structural features in the IL-la protein that readily account for its membrane association and some workers have questioned the existence of membrane-associated IL-1 (277b). Interleukin 1, whether secreted or membrane bound, is believed to exert its biological activity by binding to cell surface polypeptide receptors. Interleukin ICU and IL-lp compete for cell surface binding (53, 73, 145, 179); on some cell types IL-l/3 appears to have higher affinity, whereas on other cell types IL+ has higher affinity (73). These observations imply that there is more than one type of receptor. Interestingly, resting T-cells do not appear to have any IL-l binding sites, although receptors have been found on most IL-lresponsive T-cell clones or transformed cell lines. The IL-l receptors are few in number (typically l,OOO U/ml. The biological relevance of these concentrations is unclear, but antigenic changes attributable to IFN-7 (e.g., increased class II MHC antigen expression) have been observed in vivo during cell-mediated immune responses to antigen (71,199). An important focus of these endothelial actions of IFN-7 is their specific relevance for capacities and functions needed for lymphocyte-mediated (immune) inflammation. For example, lymphocytes have specific receptors for ICAMand MHC antigens, and IFN-7 selectively induces lymphocyte adhesion. In contrast, IFN-7 does not affect any of the coagulation-related functions of endothelium, nor does it affect functions related to acute inflammation. A second important feature of IFN-7 activity is its modulation by TNF or LT. The interactions of IFN-7 with TNF and LT are of biological interest, since these cytokines are often produced coordinately by antigenactivated T-cells (195). On endothelial cells, IFN-7 acts synergistically with TNF to increase both ICAM(Doukas and Pober, unpublished observations) and class I MHC antigen (151) expression. Also, IFN-7 acts synergistically with TNF to alter endothelial morphology from epithelioid to fibroblastoid (270); at higher
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April 199o
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concentrations of both cytokines (e.g., 100 U L929 cytotoxic activity/ml of TNF and 200 U antiviral activity of IFN-7) the combination of TNF plus IFN-7 induces a unique morphological phenotype of plump cells with extensive “dendritic” processes. We have suggested that such cells may resemble the high endothelial venular cells of antigen-activated lymph nodes. Combined treatment also produces a diminution in the rate (but not the extent) of membrane protein lateral diffusion, which is indicative of profound cellular reorganization (269). Changes in membrane protein lateral mobility were not seen after exposure to either cytokine alone. Interferon-y does not affect membrane IL-l expression (149) but has been reported to increase IL-l secretion induced by other modulators (such as endotoxin) (188). Interferon-y is not directly toxic for endothelial cells, although it is cytostatic (270) (an action shared with IFN-a and IFN-P). However, serially passaged endothelial cells may show toxicity to combinations of IFN-7 plus TNF (270). This toxic effect is manifest by cell shedding and subsequent loss of membrane integrity, similar to the response of tumor cells to TNF. The significance of this observation is not clear in that freshly isolated or early passage cultures do not manifest toxicity. It is possible that the culture conditions used to expand endothelial cells either select for a sensitive subpopulation or cause a change in phenotype that resembles tumor vasculature. Alternatively, shedding may represent an altered degree of adhesiveness to matrix (rather than a direct toxic effect), and cell death may result from detachment. However, even in early passage cells, the combination of TNF and IFN-7 is more markedly cytostatic than either cytokine alone. To date, there is no evidence that IFN-7 is angiogenic and no data regarding the effect of IFN-7 on TNF-mediated angiogenesis in vivo. It has been reported that IFN-7 inhibits angiogenesis in one in vitro assay (i.e., outgrowth of rat microvessels), an action shared with LT (283). In summary, IFN-cu and IFN-P can act on endothelial cells to inhibit cell growth and migration and increase class I MHC antigen expression. These actions are shared by IFN-7, but it also uniquely modulates a number of properties (e.g., class II MHC antigens, ICAMexpression) that enhance the ability of endothelial cells to participate in immune reactions. Also, IFN-7 shows a number of unique interactions with TNF. These actions of IFN-7 are examples of endothelial cell activation. There are few data regarding IFN-y and angiogenesis or, in the absence of TNF, as a cause of endothelial cell injury. D. Other Cytokines
With Endothelial
Actions
Most of the published data on cytokine modulation of endothelial cells has been concerned with IL-l, TNF, LT, and IFN-7. There are a few reports of biological effects by other cytokines.
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1. Interleukin
BIOLOGY
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2
Interleukin 2 is the principal autocrine and paracrine growth factor of T-cells (for review see Ref. 256). It is secreted as a 14-kDa glycoprotein by the majority of antigen-activated T-helper cells. In addition to Tcells, IL-2 also acts on B-cells, natural killer cells, and possibly macrophages. All known IL-2-responsive cell types express a 70- to 75kDa cell surface receptor (called ~70) with moderate affinity (KD ~1 nM). Biological function often shows half-maximal stimulation in the range of 10 pM; this quantitative discrepancy is resolved by the identification of a 550kDa IL-2-binding protein (also called ~55 or Tat and often referred to in the literature as “the IL-2 receptor”), which forms a noncovalent complex with ~70. The p55 protein binds IL-2 with a KD of 10 nM; however, the complex of ~55 with ~70 binds IL-2 with a KD of ~10 pM, consistent with T-cell growth stimulation. The ~55 subunit of the IL-2 receptor has been cloned; little is currently known about the structure of the ~70 subunit. In contrast to IL-l, TNF, LT, and IFN-7, IL-2 has few reported direct actions on endothelial cells. For example, IL-2 does not modulate expression of ELAM-1, ICAM-1, MHC antigens (61), leukocyte adhesion (25), or endothelial cell morphology (270). It has been reported that IL-2 increases PG12 synthesis (12,90), although we have not been able to confirm this observation (G. B. Zavoico, B. M. Ewenstein, A. I. Schafer, and J. S. Pober, unpublished observations). We have noted that IL-2 consistently enhances endothelial cell growth in the presence of endothelial cell growth factor (also called acidic fibroblast growth factor or acidic FGF) (Doukas and Pober, unpublished observations); however, IL-2 cannot replace acidic FGF in early passaged cells or in cultures maintained (and selected) for growth in acidic FGF. The half-maximal growth-promoting effect in these cultures occurs at -10 nM of IL-2, which is consistent with a p70-type receptor. Of note, it has not been possible to identify IL-2 receptors either by radioligand binding or by radioligand cross-linking, i.e., IL-2 receptors, if present, must be C 243: 1165-1172,1989. SIMS, J. E., C. J. MARCH, D. COSMAN, M. B. WIDMER, H. R. MACDONALD, C. J. McMAHAN, C. E. GRUBIN, J. M. WIGNALL, J. L. JACKSON, S. M. CALL, D. FRIEND, A. R. ALPERT, S. GILLIS, D. L. URDAL, AND S. K. DOWER. cDNA expression cloning of the IL-l receptor, a member of the immunoglobulin super family. Science Wash. DC 241: 585-589,1988. SIRONI, M., F. BREVIARIO, P. PROSERPIO, A. BIONDI, A. VECCHI, J. VAN DAMME, E. DEJANA, AND A. MANTOVANI. IL-l stimulates IL-6 production in endothelial cells. J. ImmunoC 142: 549-553,1989. SMITH, C. W., R. ROTHLEIN, B. J. HUGHES, M. M. MARISCLACO, H. E. RUDLOFF, F. C. SCHMALSTIEG, AND D. C. ANDERSON. Recognition of an endothelial determinant for CDl8dependent human neutrophil adherence and transendothelial migration. J. CZin. Invest. 82: 1746-1756, 1988. SMITH, K. A. Interleukin-2: inception, impact and implications. Science Wash. DC 240: 1169-1176,1988. SOBEL, R. A., B. W. BLANCHETTE, A. K. BHAN, AND R. B. COLVIN. The immunopathology of experimental allergic encephalomyelitis. II. Endothelial cell Ia increases prior to inflammatory cell infiltrates. J. ImmunoZ. 132: 2402-2407, 1984. SPIES, T., C. C. MORTON, S. A. NEDOSPASOV, W. FIERS, D. PIOUS, AND J. L. STROMINGER. Genes for the tumor necrosis factors ar and p are linked to the human major histocompatibility complex. Proc. NatZ. Acad. Sci. USA 83: 8699-8702, 1986. SPORN, M. B., A. B. ROBERTS, L. M. WAKEFIELD, AND R. K. ASSOIAN. Transforming growth factor-p: biological function and chemical structure. Science Wash. DC 233: 532-534,1986.
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WONG, G. H. W., AND D. V. GOEDDEL. Tumor necrosis factor a and b inhibit virus replication and synergize with interferons. Nature Lond. 323: 819-822,1986. WOODRUFF, J. J., L. M. CLARK, AND Y. H. CHIN. Specific cell-adhesion mechanisms determining migration pathways of recirculating lymphocytes. Annu. Rev. ImmunoL 5: ZOl-222,1989. YAMASAKI, K., T. TAGA, Y. HIRATA, H. YAWATA, Y. KAWANISH, B. SEED, T. TANIGUCHI, T. HIRANO, AND T. KISHIMOTO. Cloning and expression of the human interleukin-6 (BSF-Z/IFN-BZ) receptor. Science Wash. DC 241: 825-828,1988. YANAGISAWA, M., H. KURIHARA, S. KIMURA, Y. TOMOBE, M. KOBAYASHI, Y. MITSUI, Y. YAZAKI, K. GOTE, AND T. MASAKI. A novel potent vascoconstrictor peptide produced by vascular endothelial cells. Nature Lone?. 322: 411-415,1988. YU, C.-L., D. HASKARD, D. CAVENDER, AND M. ZIFF. Effects of bacterial lipopolysaccharide on the binding of lymphocytes to endothelial cell monolayers. J. Immunol 136: 569-573, 1986. YU, C.-L., D. 0. HASKARD, A. R. JOHNSON, AND M. ZIFF. Human y interferon increases binding of T lymphocytes to endothelial cells. Cell ImmunoL. 62: 554-560, 1985. ZAVOICO, G. B., B. M. EWENSTEIN, A. I. SCHAFER, AND J. S. POBER. Interleukin-1 and related cytokines enhance thrombinstimulated PGIz production in cultured endothelial cells without affecting thrombin-stimulated von Willebrand factor secretion or platelet-activating factor biosynthesis. J. ImmunoZ. 142: 3993-3999,1989.
ZETTER, B. R. Migration of capillary endothelial cells is stimulated by tumour-derived factors. Nature Land 285: 41-43,198O. 304. ZSEBO, K. M., V. N. YUSCHENKOFF, S. SCHIFFER, D. CHANG, E. MCCALL, C. A. DINARELLO, M. A. BROWN, B. ALTROCK, AND G. C. BAGBY, JR. Vascular endothelial cells and granulopoiesis: interleukin-1 stimulates release of G-CSF and GM-CSF. BZood 71: 99-103,1988. 303.
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in U.S.A.
Cytokines and Endothelial JORDAN Departments
of Pathology,
Brigham
S. POBER
and Wmen
AND RAMZI
‘s Hospital
Cell Biology S. COTRAN
and Harvard
Medical
I. Introduction ............................................................................... II. Specific Cytokine Actions on Endothelial Cells ................................................ A. Interleukinl ............................................................................ ................................................... B. Tumor necrosis factor and lymphotoxin C. Interferons ............................................................................. .................................................. D. Other cytokines with endothelial actions ................................... III. Cytokine Actions on Endothelium in Pathological Processes A. Acuteinflammation ..................................................................... B. Shwartzmanreaction .................................................................... ................................................................. C. Delayed hypersensitivity D. Normallymphocyterecirculation ......................................................... E. Vascular leakage ........................................................................ ....................................................... F. Autoimmunity and vascular injury G. Transplantation ......................................................................... H. Angiogenesis ............................................................................ IV. Conclusions ................................................................................
I. INTRODUCTION
The effector phase of an immune response involves the secretion of protein mediators by antigen-stimulated T lymphocytes, which serve to recruit and activate the various responsive cell populations that comprise the inflammatory infiltrate. Some of these responsive cell populations, most notably mononuclear phagocytes, in turn secrete additional protein mediators that influence the reaction. These lymphocyte-derived and mononuclear phagocyte-derived mediators were called “lymphokines” and “monokines,” respectively. When it was discovered that cells not traditionally part of the immune system could also secrete similar or identical protein mediators, these molecules were collectively renamed as “cytokines” (55). Although there is no universally accepted rigorous definition of a cytokine, to be considered to be a cytokine a protein I) must mediate some aspect of inflammation and 2) must be elicited as part of the immune response to antigen. This definition does not exclude the possibility of secretion in response to other stimuli, and, in fact, for mononuclear phagocyte-derived mediators, microorganisms and their products (e.g., endotoxins) may be far more potent stimulators than antigen-generated signals. Cytokines are not always secreted; in some cases they may be expressed on the cell surface of the stimulated cell. However, whether secreted or surface expressed, cytokines share a common mode of action: they bind to specific protein receptors on the surface of their target cell. Cytokines have no enzymatic activities or chemical reactivities but indirectly function through altering the 0031-9333/90
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behavior of a target cell. In this sense, cytokines are similar to hormones. The target cell for cytokines may be the cell of origin (autocrine actions), nearby cells (paracrine actions), or, as for true hormones, distant target cells in other organs, such as liver or brain (endocrine actions). There are two other general features of cytokine function. First, one cytokine often causes the secretion of a second cytokine by its target cell and so on. This phenomenon has been described as a cytokine cascade. Second, individual cytokines often modulate the actions of other cytokines on the same target cell. Such interactions may be mutually inhibitory, additive, synergistic, or even result in novel effects not seen with either individual cytokine. Thus the precise biological effect of a cytokine will be determined by the milieu in which it acts. Many of the early studies on cytokines were performed in vitro using leukocytes isolated from blood or lymphoid organs. This led to the conclusion that the principal targets of cytokine actions were leukocytes. At one point, the narrow view that cytokines were leukocyte-derived mediators that act on other leukocytes gave rise to the alternative name of “interleukins” for these molecules and the assignment of numbers within the so-called family of interleukins to distinguish among the different mediators (e.g., interleukin 1, interleukin 2) (1). It is now apparent that tissue cells other than leukocytes are important targets of cytokines and, in some instances, may be the major targets. Among the tissue cells it is now appreciated that the endothelial lining of blood vessels is a critical focus of many cytokine actions. In retrospect, this is not sur427
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prising. Endothelium is the gatekeeper of the tissues from the perspective of the bloodstream, and alterations of the endothelium are important determinants in regulating traffic of circulating cells and molecules into the tissues (for review see Ref. 59). The gatekeeping function of endothelium has especially focused attention on the microvasculature and particularly on the postcapillary venular segments where leukocyte trafficking and macromolecular extravasation are known to occur (174). In general, there are three separate responses of microvascular endothelium in vivo that may be cytokine related. First, endothelial cells may be injured during immune responses. For example, the rejection of transplanted organs appears primarily to be an immune response against foreign endothelial cells (182). In this context, it is possible that endothelial injury may result directly from cytokine binding to endothelial cell receptors. In the case of endothelium, injury may manifest as frank denudation, focal cell necrosis, or more subtle loss of integrity, resulting in varying degrees of “dysfunction” (105). Second, endothelial cells may migrate, proliferate, and form new blood vessels (88, 89). The formation of new blood vessels by outgrowth of existing vessels, called angiogenesis, is a key component of the tissue remodeling that accompanies chronic inflammation, and there is considerable recent evidence that certain cytokines can initiate angiogenesis (i.e., act as angiogenic factors). Third, endothelial cells may acquire the capacity to perform new functions without evidence of cell injury or cell division. This process, which we have called activation, is the result of quantitative changes in certain gene products and most certainly is a response to cytokines (61, 217). Because activation is defined by altered capacities and functions, it follows that there may be numerous distinct (but potentially overlapping) states of activation. Moreover, the distinction between activation and proliferation may be artificial and is certainly not exclusive; indeed, the distinctions between growth factors and cytokines are quite arbitrary and difficult to define. Finally, although a clear cut distinction exists between injury and activation, the functions displayed by an activated endothelial cell may well lead to endothelial injury through indirect mechanisms (see sect. III). The last topic we consider is how endothelial cell responses to cytokines may be studied. Endothelial cell cultures (102, 130) have been an invaluable tool in defining the responses to cytokines, and much of the work we review here is based on such experiments. A cell culture system is infinitely simpler than in vivo settings and thus much more amenable to analysis. However, the types of large vessel and microvascular endothelial cells in culture do not necessarily share the characteristics of the particular type of endothelial cell of greatest interest, i.e., the postcapillary venular endothelium. Moreover, there may well be organ-specific differences among endothelial cells that are retained by cultured cells. Therefore umbilical vein-derived or adipose-derived endothelium may be a poor model for renal or
RAMZI
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brain endothelium. Of even greater concern is that particular differentiated features of endothelial cell behavior may be lost on isolation for cell culture or overwhelmed by the conditions and factors needed to propagate cultured cells. In short, it is always necessary to ask whether a particular effect observed in a particular culture system is an accurate model of the in vivo response observed in the venules of the vascular bed of interest. For these reasons, experimental animal models to study cytokine effects have been developed, and attempts to document some of these effects in human pathological conditions have been conducted. We have found that immunocytochemical demonstration of activation antigens, applied to organ culture systems and to tissue biopsies, is an invaluable tool for making such connections. II.
SPECIFIC
CYTOKINE
ACTIONS
ON ENDOTHELIAL
CELLS
In this section we review the specific actions of a number of cytokines on endothelial cells in vitro and, where known, in vivo. We consider both the actions of individual cytokines and of cytokines in combination. Published observations as well as unpublished data from the authors’ laboratories are discussed. In section III, we synthesize these observations by considering a number of pathological processes in which cytokinemediated responses of endothelium may be of particular import. A. Interleukin
I
Interleukin 1 (IL-l) is a pleiotropic inflammatory mediator, with numerous biological effects on many different cell types (209, 210). It is therefore not surprising that it has been repeatedly rediscovered in a variety of different contexts. The first described activity of IL-1 was as a costimulator of T lymphocytes (100). The standard bioassay for IL-1 is synergistic stimulation of murine thymocyte proliferation when combined with a mitogenic plant lectin, such as concanavalin A or phytohemagglutinin. Because endotoxin may exert similar effects, an endotoxin-resistant mouse strain (e.g., CSH-HEJ) is conveniently selected as the source of thymocytes. An alternative bioassay is to use costimulation of certain murine T-cell clones, such as DlO.G4.1, which have greater specificity and sensitivity for IL-1 than thymocytes (144). The most readily available source of biological IL-1 is conditioned medium of mononuclear phagocytes exposed for 12-24 h to bacteria or endotoxin. Mononuclear phagocyte-derived IL-1 consists of two major polypeptides, each of -17 kDa, with isoelectric points of near neutrality (the predominant species) and near pH 5.0 (the lesser species) (173). There are at least two distinct genes, the products of which have IL-1 bioactivity. Interleukin la, the first one cloned in mouse (168), encodes for the ~15.0 species (44), and IL-l& the
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first one cloned in human (13), encodes for the p1 7.0 species (45). There is only limited homology between the amino acid sequences of IL-la and IL-l& Both IL-1 genes actually encode for primary translation products of ~33-34 kDa; the mature IL-l species are derived from the carboxy-terminal halves of the putative precursors (44,45). The 33-kDa species of IL-la is biologically active, whereas IL-lp only gains activity when the amino-terminal half is removed (173). Neither IL-1 gene product contains any membrane-spanning sequence or putative leader sequence typically involved in secretion. In some cases, IL-l bioactivity is retained in association with the cell of origin, can be assayed on intact (or even fixed intact) cells, and can be isolated with the plasma membrane of subfractionated cells (148). Such “membrane IL-l” appears to consist exclusively of IL-la (58, 149). There are no structural features in the IL-la protein that readily account for its membrane association and some workers have questioned the existence of membrane-associated IL-1 (277b). Interleukin 1, whether secreted or membrane bound, is believed to exert its biological activity by binding to cell surface polypeptide receptors. Interleukin ICU and IL-lp compete for cell surface binding (53, 73, 145, 179); on some cell types IL-l/3 appears to have higher affinity, whereas on other cell types IL+ has higher affinity (73). These observations imply that there is more than one type of receptor. Interestingly, resting T-cells do not appear to have any IL-l binding sites, although receptors have been found on most IL-lresponsive T-cell clones or transformed cell lines. The IL-l receptors are few in number (typically l,OOO U/ml. The biological relevance of these concentrations is unclear, but antigenic changes attributable to IFN-7 (e.g., increased class II MHC antigen expression) have been observed in vivo during cell-mediated immune responses to antigen (71,199). An important focus of these endothelial actions of IFN-7 is their specific relevance for capacities and functions needed for lymphocyte-mediated (immune) inflammation. For example, lymphocytes have specific receptors for ICAMand MHC antigens, and IFN-7 selectively induces lymphocyte adhesion. In contrast, IFN-7 does not affect any of the coagulation-related functions of endothelium, nor does it affect functions related to acute inflammation. A second important feature of IFN-7 activity is its modulation by TNF or LT. The interactions of IFN-7 with TNF and LT are of biological interest, since these cytokines are often produced coordinately by antigenactivated T-cells (195). On endothelial cells, IFN-7 acts synergistically with TNF to increase both ICAM(Doukas and Pober, unpublished observations) and class I MHC antigen (151) expression. Also, IFN-7 acts synergistically with TNF to alter endothelial morphology from epithelioid to fibroblastoid (270); at higher
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April 199o
CYTOKINES
AND
ENDOTHELIAL
concentrations of both cytokines (e.g., 100 U L929 cytotoxic activity/ml of TNF and 200 U antiviral activity of IFN-7) the combination of TNF plus IFN-7 induces a unique morphological phenotype of plump cells with extensive “dendritic” processes. We have suggested that such cells may resemble the high endothelial venular cells of antigen-activated lymph nodes. Combined treatment also produces a diminution in the rate (but not the extent) of membrane protein lateral diffusion, which is indicative of profound cellular reorganization (269). Changes in membrane protein lateral mobility were not seen after exposure to either cytokine alone. Interferon-y does not affect membrane IL-l expression (149) but has been reported to increase IL-l secretion induced by other modulators (such as endotoxin) (188). Interferon-y is not directly toxic for endothelial cells, although it is cytostatic (270) (an action shared with IFN-a and IFN-P). However, serially passaged endothelial cells may show toxicity to combinations of IFN-7 plus TNF (270). This toxic effect is manifest by cell shedding and subsequent loss of membrane integrity, similar to the response of tumor cells to TNF. The significance of this observation is not clear in that freshly isolated or early passage cultures do not manifest toxicity. It is possible that the culture conditions used to expand endothelial cells either select for a sensitive subpopulation or cause a change in phenotype that resembles tumor vasculature. Alternatively, shedding may represent an altered degree of adhesiveness to matrix (rather than a direct toxic effect), and cell death may result from detachment. However, even in early passage cells, the combination of TNF and IFN-7 is more markedly cytostatic than either cytokine alone. To date, there is no evidence that IFN-7 is angiogenic and no data regarding the effect of IFN-7 on TNF-mediated angiogenesis in vivo. It has been reported that IFN-7 inhibits angiogenesis in one in vitro assay (i.e., outgrowth of rat microvessels), an action shared with LT (283). In summary, IFN-cu and IFN-P can act on endothelial cells to inhibit cell growth and migration and increase class I MHC antigen expression. These actions are shared by IFN-7, but it also uniquely modulates a number of properties (e.g., class II MHC antigens, ICAMexpression) that enhance the ability of endothelial cells to participate in immune reactions. Also, IFN-7 shows a number of unique interactions with TNF. These actions of IFN-7 are examples of endothelial cell activation. There are few data regarding IFN-y and angiogenesis or, in the absence of TNF, as a cause of endothelial cell injury. D. Other Cytokines
With Endothelial
Actions
Most of the published data on cytokine modulation of endothelial cells has been concerned with IL-l, TNF, LT, and IFN-7. There are a few reports of biological effects by other cytokines.
CELL
1. Interleukin
BIOLOGY
435
2
Interleukin 2 is the principal autocrine and paracrine growth factor of T-cells (for review see Ref. 256). It is secreted as a 14-kDa glycoprotein by the majority of antigen-activated T-helper cells. In addition to Tcells, IL-2 also acts on B-cells, natural killer cells, and possibly macrophages. All known IL-2-responsive cell types express a 70- to 75kDa cell surface receptor (called ~70) with moderate affinity (KD ~1 nM). Biological function often shows half-maximal stimulation in the range of 10 pM; this quantitative discrepancy is resolved by the identification of a 550kDa IL-2-binding protein (also called ~55 or Tat and often referred to in the literature as “the IL-2 receptor”), which forms a noncovalent complex with ~70. The p55 protein binds IL-2 with a KD of 10 nM; however, the complex of ~55 with ~70 binds IL-2 with a KD of ~10 pM, consistent with T-cell growth stimulation. The ~55 subunit of the IL-2 receptor has been cloned; little is currently known about the structure of the ~70 subunit. In contrast to IL-l, TNF, LT, and IFN-7, IL-2 has few reported direct actions on endothelial cells. For example, IL-2 does not modulate expression of ELAM-1, ICAM-1, MHC antigens (61), leukocyte adhesion (25), or endothelial cell morphology (270). It has been reported that IL-2 increases PG12 synthesis (12,90), although we have not been able to confirm this observation (G. B. Zavoico, B. M. Ewenstein, A. I. Schafer, and J. S. Pober, unpublished observations). We have noted that IL-2 consistently enhances endothelial cell growth in the presence of endothelial cell growth factor (also called acidic fibroblast growth factor or acidic FGF) (Doukas and Pober, unpublished observations); however, IL-2 cannot replace acidic FGF in early passaged cells or in cultures maintained (and selected) for growth in acidic FGF. The half-maximal growth-promoting effect in these cultures occurs at -10 nM of IL-2, which is consistent with a p70-type receptor. Of note, it has not been possible to identify IL-2 receptors either by radioligand binding or by radioligand cross-linking, i.e., IL-2 receptors, if present, must be C 243: 1165-1172,1989. SIMS, J. E., C. J. MARCH, D. COSMAN, M. B. WIDMER, H. R. MACDONALD, C. J. McMAHAN, C. E. GRUBIN, J. M. WIGNALL, J. L. JACKSON, S. M. CALL, D. FRIEND, A. R. ALPERT, S. GILLIS, D. L. URDAL, AND S. K. DOWER. cDNA expression cloning of the IL-l receptor, a member of the immunoglobulin super family. Science Wash. DC 241: 585-589,1988. SIRONI, M., F. BREVIARIO, P. PROSERPIO, A. BIONDI, A. VECCHI, J. VAN DAMME, E. DEJANA, AND A. MANTOVANI. IL-l stimulates IL-6 production in endothelial cells. J. ImmunoC 142: 549-553,1989. SMITH, C. W., R. ROTHLEIN, B. J. HUGHES, M. M. MARISCLACO, H. E. RUDLOFF, F. C. SCHMALSTIEG, AND D. C. ANDERSON. Recognition of an endothelial determinant for CDl8dependent human neutrophil adherence and transendothelial migration. J. CZin. Invest. 82: 1746-1756, 1988. SMITH, K. A. Interleukin-2: inception, impact and implications. Science Wash. DC 240: 1169-1176,1988. SOBEL, R. A., B. W. BLANCHETTE, A. K. BHAN, AND R. B. COLVIN. The immunopathology of experimental allergic encephalomyelitis. II. Endothelial cell Ia increases prior to inflammatory cell infiltrates. J. ImmunoZ. 132: 2402-2407, 1984. SPIES, T., C. C. MORTON, S. A. NEDOSPASOV, W. FIERS, D. PIOUS, AND J. L. STROMINGER. Genes for the tumor necrosis factors ar and p are linked to the human major histocompatibility complex. Proc. NatZ. Acad. Sci. USA 83: 8699-8702, 1986. SPORN, M. B., A. B. ROBERTS, L. M. WAKEFIELD, AND R. K. ASSOIAN. Transforming growth factor-p: biological function and chemical structure. Science Wash. DC 233: 532-534,1986.
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