Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952
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ABSTRACT |
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Intestinal inflammation has traditionally been viewed as a process in which effector immune cells cause the destruction of other mucosal cells that behave as passive bystander targets. Progress in understanding the process of intestinal inflammation has led to a much broader and more integrated picture of the various mucosal components, a picture in which cytokines, growth factors, adhesion molecules, and the process of apoptosis act as functional mediators. Essentially all cellular and acellular components can exert immunelike activities, modifying the classical concept of selected immune cells acting on all other cells that has been the dogma of immunologically mediated tissue damage for decades. The existence of specialized communication pathways between epithelial cells and T cells is well documented, including abnormal epithelial cell-mediated T cell activation during inflammation. Mesenchymal cells contribute to fibrosis in the inflamed gut but are also responsible for retention and survival of leukocytes in the mucosa. In chronically inflamed intestine the local microvasculature displays leukocyte hyperadhesiveness, a phenomenon that probably contributes to persistence of inflammation. The extracellular matrix regulates the number, location, and activation of leukocytes, while metalloproteinases regulate the quantity and type of deposited matrix proteins. This evidence from the intestinal system, consolidated with the use of data from other organs and systems, reveals a rich network of reciprocal and finely orchestrated interactions among immune, epithelial, endothelial, mesenchymal, and nerve cells and the extracellular matrix. Although these interactions occur under normal conditions, the dysfunction of any component of this highly integrated mucosal system may lead to a disruption in communication and result in pathological inflammation.
epithelial cells; mesenchymal cells; endothelial cells; extracellular matrix
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ARTICLE |
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INFLAMMATION is by far the most common type of response that the body employs as a defense mechanism against the constant and massive challenges originating from the surrounding environment. The frequency and degree of the inflammatory response depend, at least in part, on the area of the body facing the challenge. Because of its enormous mucosal surface, which is continuously exposed to a myriad of antigenic, mitogenic, mutagenic, and toxic stimuli, the gastrointestinal tract is clearly more susceptible to such inflammatory responses. Even under normal conditions the intestinal mucosa displays a state of "physiological inflammation," manifested by the presence of abundant leukocytes in the intraepithelial and subepithelial compartments (16). This is largely the consequence of an immune response to the dietary and bacterial antigens found in the lumen and has helped to form a concept of the gut as the largest lymphoid organ of the body (8). Because of this connotation, it has become an established notion that when a true inflammatory response, or "pathological inflammation," occurs in the intestine such a response is dominated by the cells of the mucosal immune system. According to this theory, activated immune cells, primarily represented by neutrophils, macrophages, and cytotoxic T cells, play the role of aggressors that attack and destroy nearby cells, either directly through physical contact or indirectly through the release of soluble factors such as reactive oxygen and nitrogen metabolites, cytotoxic proteins, lytic enzymes, or cytokines (18, 27). Implicit in this model is the idea that nonimmune mucosal cells behave as passive "bystanders," waiting to be injured and eventually die at the hands of an all powerful army of effector immune cells (Fig. 1). This simple unidirectional model is intuitive, answers the plead-for one cause-one effect relationship, and is convenient, since it is merely necessary to understand how mucosal immunity works to explain most types of intestinal inflammation. Unfortunately, this view is also likely to be too restrictive, naive, and incorrect. The unidirectional model is increasingly challenged by emerging evidence showing that all cell types populating the mucosa have an active role in intestinal immunity and inflammation. Epithelial, endothelial, mesenchymal, and nerve cells display broad and previously unsuspected effector and regulatory functions, including immunelike functions, and interact intimately with lymphoid cells. Even acellular components appear to play an active and surprisingly broad role, typically exemplified by the immunoregulatory activity of the extracellular matrix under both normal and inflammatory conditions (58, 64). As a consequence of this multiplicity and reciprocity of cellular actions in the mucosa, a multidirectional model of interactions between effector cells and target cells in normal and inflamed mucosa makes practical sense and probably more closely reflects reality (Fig. 2). Furthermore, a multidirectional model may be especially appropriate to investigate the mechanisms of chronic intestinal inflammation, as in inflammatory bowel disease (IBD), in which reactive behavior by nonimmune cells underlies the symptoms and structural changes observed in patients, such as pain, dismotility, fibrosis, stricture, and fistula formation, obstruction, and neoplastic transformation.
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The concept of an integrated and tightly regulated multicellular response in pathological processes in general, and inflammation in particular, has been applied to several organs and tissues, but only very recently has this concept been considered in the gut (19). Thus it is not surprising that there is a remarkable paucity of information on cellular interactions in complex inflammatory diseases, such as Crohn's disease and ulcerative colitis, and there are essentially no data derived from animal models of IBD. This makes it difficult to understand the cellular and molecular mechanisms underlying gut inflammation in humans. Therefore, some of the discussion of this review refers to cellular systems and organs outside of the gastrointestinal tract and to data, often of a preliminary nature, generated from a limited number of laboratories. Three specific aspects are addressed within the scope of this review: the types of immune-nonimmune cell interactions, the molecular (cytokines, growth factors, adhesion molecules) and functional (activation, proliferation, and apoptosis) bases for interaction, and the integration of cell interactions.
Among the various immune-nonimmune cell interactions occurring in the gut, the functional communication existing between epithelial cells and lymphocytes has been studied extensively. The concept of an immunological regulation of epithelial function is over a decade old (10) and was consolidated only after the demonstration of a well-defined antigen-presenting activity by rodent and human epithelial cells for T cells (6, 47). More recent work showing that human intestinal epithelial cells produce cytokines regulating the proliferation of intestinal lamina propria mononuclear cells (71) and express functional cytokine receptors for several T cell-derived cytokines (60) has further strengthened the concept of an exchange of regulatory signals between the epithelial and immune compartments of the mucosa. This reciprocal exchange of regulatory signals is probably altered during intestinal inflammation, as epithelial cells express de novo or upregulate expression of activation and cell adhesion molecules, such as HLA-DR antigens (63) and intercellular adhesion molecule-1 (32), and secrete a variety of proinflammatory cytokines affecting leukocyte activity (37). Another way in which epithelial cells may participate in or even induce intestinal inflammation is through defects of their basic function. This could be an explanation for the well-documented increase in intestinal permeability in Crohn's disease and intestinal infections (5) or the defective induction of suppressor T cells in patients with IBD (46).
Of the many types of nonimmune cells, those of mesenchymal origin, such as fibroblasts, myofibroblasts, and muscle cells, have traditionally been viewed as purely structural, designed to fill the space around other more functionally important cells or to perform mundane activities such as collagen deposition (44). This unsophisticated view no longer fits with evidence derived from studies indicating a far broader and more refined function for mesenchymal cells (69). For instance, intestinal electrolyte transport occurring in response to inflammatory mediators is modulated by fibroblastic cells (2). These likely represent a group of cells that are highly heterogeneous and selectively distributed throughout the mucosa, as suggested by the subepithelial localization of stellate myofibroblasts, a strategic location where they can receive, regulate, and transmit immune cell-derived signals to adjacent epithelial cells (30). Evidence for the heterogeneity of phenotype and function of mucosal mesenchymal cells is still limited, since these cells have only recently received attention, but information from other organs and systems is quite convincing (74). Mesenchymal cells from normal and inflamed tissues produce various cytokines (9, 14, 41), express cytokine receptors (28), and physically interact with immune cells (40), an activity that is in turn modulated by cytokines (54). Similar results have been obtained from murine and human studies using intestinal mesenchymal cells (31, 38, 52). Another aspect directly relevant to cell-cell interactions during inflammation is the ability of mesenchymal cells to prolong T cell survival (62). Human intestinal fibroblasts also possess this property (35), which, complemented with their adhesiveness for T cells (36), may have profound implications for the duration of an intestinal inflammatory process. This particular aspect, combined with the capacity of mesenchymal cells to produce proinflammatory cytokines, raises a provocative question. Which cells are actually responsible for the chronicity of inflammation, immune cells activated by an unknown primary antigen or byproducts of surrounding nonimmune cells, mesenchymal cells activated by immune cell- or self-derived cytokines, or perhaps both cell types stimulating one another in a perpetuating unregulated loop? This critical question waits for answers from ongoing studies.
A cell-cell interaction of great importance to the maintenance of
mucosal immune homeostasis and sine qua non for the initiation of
pathological gut inflammation is that between leukocytes and the local
microvascular endothelium (55). Each vascular bed displays unique
characteristics, with cell heterogeneity within different vessels of
the same organ and between segments of the same vessel (75).
Consequently, information derived from large vascular structures does
not apply to the intestinal microvasculature, which displays specific
features in response to inflammation (26). The key elements that
regulate endothelial-leukocyte interactions are fairly well defined and
include the state of differentiation and activation of endothelial
cells (1), expression of cell adhesion molecules by both cell types
(21), and the spectrum of cytokines they produce (43). Leukocyte
migration to specific tissues, including the mucosal microcirculation,
occurs through high endothelial venules (HEV), specialized endothelial
cells that are probably involved in inflammatory diseases (23). A key
cell adhesion molecule expressed by gut HEV is the mucosal vascular
addressin MAdCAM-1, a receptor for the
4
7-integrin present on circulating lymphocytes and proposed to mediate their selective migration to the gut (15). A large body of evidence supports
the view that reciprocal signaling between endothelial cells and
leukocytes also involves cytokines produced by and acting on both
cells. T cell- derived cytokines induce phenotypic and functional
changes in endothelial cells (20), and monocyte/macrophage-derived tumor necrosis factor-
induces them to produce interleukin-1 (50).
Cytokines selectively increase leukocyte adhesiveness to vascular
endothelium, as interleukin-1 does for polymorphonuclear cells and
monocytes (3) and interleukin-4 does for T cells, but not for
neutrophils (68). All of these interactions are relevant to
inflammation and contribute to tissue damage (73).
Until recently, evidence that the above phenomena actually take place in the intestine was lacking due to a lack of experimental systems to directly evaluate relevant cell types. In the last two years methods have been established allowing the isolation and study of human intestinal microvascular endothelial cells (HIMEC) (4, 29, 33). Particularly exciting are data showing that HIMEC derived from IBD mucosa display enhanced adhesiveness for leukocytes compared with microvascular endothelium from normal mucosa (4). It is particularly significant that enhanced leukocyte adhesiveness persists regardless of whether IBD HIMEC are kept in culture, suggesting the existence of permanent functional alterations of the microvasculature in chronically inflamed gut mucosa. Knowledge derived from leukocyte endothelial interaction in the gut is fundamental not only to the understanding of the cellular and molecular mechanisms controlling vascular permeability and angiogenesis (12) but also to the development of novel forms of therapy for intestinal inflammation (51, 57, 70).
The above discussion shows how the misconception that immune cells alone control immunity and inflammation is being gradually modified by evidence that other cell types actively participate in those responses. An acellular component, the extracellular matrix (ECM), must be added to the growing list of nonimmune cellular elements involved in immunity and inflammation. All immune-nonimmune cell interactions mentioned so far occur in the midst of a complex mixture of proteins including fibronectin, collagen, laminin, thrombospondin, tenascin, entactin, proteoglycans, and others (58). In the gut mucosa these proteins occupy distinct domains that can be roughly divided into a compact laminar structure represented by the basement membrane and a diffuse network surrounding lymphoid, mesenchymal, vascular, and nerve cells. To a large extent, the composition of the ECM determines what cell surface receptors are expressed, which in turn controls the number and types of cells locally retained. This is especially important during inflammation, when the ECM plays a major role in regulating the number, location, and state of activation of leukocytes (13, 22). These interactive events are mediated through specific mononuclear cell surface receptors represented by integrins, CD44, CD26, and CD37 (64). Further interaction between the ECM and immune cells occurs through the action of matrix metalloproteinases (MMP), a family of zinc-containing endoproteinases produced by macrophages and T cells and capable of degrading connective tissue, enhancing chemotaxis and cell adhesion, aiding extravascular tissue access, and facilitating secretion of membrane-anchored cytokines (24). There is preliminary evidence suggesting that MMP are involved in intestinal inflammation. Granulation tissue next to IBD ulcers contains MMP1 and MMP3 mRNA (61), and activation of lamina propria T cells can lead to proteolytic degradation of mucosal ECM (53).
Extremely limited information exists on the amount, composition, and
function of ECM in intestinal inflammation. In situ studies using
Crohn's disease and ulcerative colitis tissue sections show that in
both forms of IBD there are significantly increased levels of
procollagen mRNA, but the patterns of collagen deposition differ between the two diseases (45). Fibroblasts from strictured segments of
Crohn's disease-affected bowel produce significantly elevated amounts
of collagen type III and display a heightened response to transforming
growth factor- induction (65). Only preliminary data are available
on the function of mucosal ECM in inflammation. Using matrix proteins
deposited by cultured mucosal fibroblasts, Musso et al. (48) have shown
that adhesion of T cells to this ECM is significantly greater with
fibroblasts derived from IBD and that T cell adhesion can be augmented
by pretreating the fibroblasts with proinflammatory cytokines. The
cause and mechanisms of these provocative observations remain to be
elucidated, but they suggest that considerable attention should be paid
to the communication and exchanges between immune cells and ECM in
intestinal inflammation.
The participation of the ECM expands the dimension of biological interactions in intestinal immunity and inflammation, which, in addition to traditional interactions between immune cells, now consists of interactions between immune and nonimmune cells, immune cells and ECM, and nonimmune cells and ECM. When these interactions occur in the normal mucosa, the result is intestinal homeostasis, which is seen as physiological inflammation (Fig. 3). Consequently, pathological inflammation can be viewed as the product of abnormal or disrupted interactions between two or more of the immune or nonimmune mucosal components. In cases of chronic intestinal inflammation such as IBD, multiple components are probably involved in anomalous communications among themselves. Accepting this hypothesis, a new challenge is to determine what precise elements mediate the actual communication and integrate exchanges among the various cellular and acellular constituents of the mucosa under both physiological and pathological conditions. These elements are multiple and different in nature: some are elaborated by the cells themselves, such as cytokines, growth factors, and adhesion molecules (Fig. 2); others are events triggered by cell interactions, such as migration, activation, proliferation, and apoptosis; and others are preexisting elements of the mucosa, such as the enteric nervous system. Because the focus of this review is on the importance of interactions to intestinal inflammation rather than the specific mechanisms of interaction during inflammation, only a few comments are made with regard to the above regulatory elements. The crucial role of cytokines and growth factors in intestinal inflammation is firmly established (17), and mounting evidence predicts a similarly crucial role for adhesion molecules (39, 42, 49). The explosion of knowledge in the field of apoptosis (67) is gradually reaching the gut (72), where the phenomenon of programmed cell death appears to have distinct features (7, 66), and defects in apoptosis may be implicated in chronic inflammatory conditions (34). Finally, the nervous system may represent the ultimate and most efficient integrating element through its extremely rich network of enteric fibers and extensive array of neurotransmitters (25). In fact, the enteric nervous system may mimic in the mucosa the intricacy of regulatory mechanisms it exerts in the endocrine and immune systems (59) and may mediate broad and potent modulatory activities in both acute and chronic intestinal inflammation (11).
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In a recent review, Podolsky (56) indicated that there are many questions, but few answers, concerning our understanding of the regulation of intestinal epithelial cell proliferation. If a single biological phenomenon is so complex and challenging, the reader may wonder how one can possibly study all mucosal cell types and hope to fully understand their functions and interactions, not to mention the countless abnormalities sure to be found in intestinal inflammation. These concerns are legitimate, but a Cartesian approach to split, divide, and pick the simplest problem first, combined with the careful choice of an integrated experimental system, will duly reward the dedicated investigator.
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ACKNOWLEDGEMENTS |
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I thank Drs. A. D. Levine and S. Chakravarti for helpful discussion of the manuscript.
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FOOTNOTES |
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Some of the research cited in this article was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-30399 and DK-50984 and by the Crohn's and Colitis Foundation of America, Inc.
Address reprint requests to Division of Gastroenterology (BRB 425), Case Western Reserve Univ. School of Medicine, 10900 Euclid Ave., Cleveland, Ohio 44106-4952.
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