© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 29, 26-30,
2001
© 2001 Oxford University Press
Inflammatory Cytokines and Mucosal Injury
Affiliations of authors: Howard Hughes Medical Institute, Indiana University School of Medicine, Section of Pediatric Hematology/Oncology, Herman B Wells Center for Pediatric Research, and Department of Pediatrics, Indiana University School of Medicine, Indianapolis.
Correspondence to:David A. Williams, M.D., Herman B Wells Center for Pediatric Research, 1044 West Walnut St., Rm. 402, Indianapolis, IN 46202 (e-mail: dwilliam{at}iupui.edu).
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ABSTRACT |
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 TopNotes Abstract IntroductionAbnormal Host Immune Responses...Ibd in IL-10-Deficient MiceIL-11 in the Treatment...Relationship of Inflammatory...Future Research DirectionsReferences |
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The cause of mucosal injury in inflammatory bowel disease (IBD) is not clear but likely involves infectious agents or other toxins followed by an abnormal immune response in genetically susceptible individuals. The inflammatory cytokines appear to play a key role in both the susceptibility of some individuals and the tissue damage that accompanies IBD. The generation of transgenic and gene-targeted (knockout) animals has provided invaluable information regarding the cytokines and cellular immune effectors that are important in IBD. Information from these and other preclinical animal models, such as those involving interleukin 11, has led to human trials testing novel therapies for IBD and other diseases in which inflammation of the gut mucosa is an important component. Thus, expression of inflammatory cytokines appears to be an important target for the development of novel therapies for IBD and other diseases in which intestinal mucosal damage occurs, such as mucositis and graft-versus-host disease. [J Natl Cancer Inst Monogr 2001;29:26–30]
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INTRODUCTION |
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TopNotesAbstractIntroductionAbnormal Host Immune Responses...Ibd in IL-10-Deficient MiceIL-11 in the Treatment...Relationship of Inflammatory...Future Research DirectionsReferences |
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The etiology of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, remains unknown and is likely multifactorial. General theories of contributing factors include persistent or inciting infectious agents, a defective mucosal barrier, and abnormal host immune responses to infection or environmental antigens (1). Genetic epidemiologic studies and more recent genome mapping studies (2,3) indicate that inherited factors may contribute to individual susceptibility to IBD. While little direct evidence exists supporting the role of abnormal host immune response in IBD in humans, a large body of data in experimental animal models and phenotypes of animals deficient in specific genes generated by homologous recombination methods suggests that the immune system plays a key role in either initiating or maintaining the disease state (45). These observations have led to clinical studies targeting modification of specific immune regulators (Table 1
). In the case of interleukin (IL)-11, a pleiotropic cytokine of mesenchymal origin, observations in animal studies of mucosal damage by chemotherapy agents led to subsequent human trials in IBD (6).
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ABNORMAL HOST IMMUNE RESPONSES IN MUCOSAL DISEASE |
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TopNotesAbstractIntroductionAbnormal Host Immune Responses...Ibd in IL-10-Deficient MiceIL-11 in the Treatment...Relationship of Inflammatory...Future Research DirectionsReferences |
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A variety of studies in animals have led to the hypothesis that an abnormal host immune response is an essential feature of mucosal disease [reviewed in (7)]. These studies suggest that various initiating events in a genetically susceptible individual lead to an imbalance between proinflammatory and anti-inflammatory cytokines (Table 2
). T-helper (CD4) cells under the stimulation of specific cytokines differentiate into two subsets of cells called TH1 or TH2 [reviewed in (8)]. In many studies, T cells of the TH1 subset appear to be an important mediator of mucosal inflammation. TH1 cells are induced by IL-12 and interferon gamma (IFN 
), whereas TH2 cells are induced by IL-10 and IL-4. TH1 cells mediate various cellular immune responses, including macrophage activation, leading to the production of proinflammatory cytokines, including IFN , IL-2, IL-12, tumor necrosis factor (TNF), nitrous oxide (NO), and IL-1. TH2 cells mediate hypersensitivity responses, reduce macrophage activation, and stimulate antibody responses. The resulting effects of stimulation by T lymphocytes on a variety of other inflammatory cells (mast cells, neutrophils, and natural killer cells) lead to the production of a large number of soluble inflammatory mediators that are increased in IBD, including arachidonic acid metabolites, toxic phagocytic products (oxygen metabolites, nitric oxide, collagenases, etc.), toxic lymphocyte products, neuropeptides, and various components of the plasma proteolytic cascades (1,4,5,7,9).
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The generation of various gene knockout and transgenic mouse strains has contributed substantial new understanding to the role of T cells in the development of IBD [Table 3
and reviewed in (9)]. In particular, IBD develops in mice with alterations in T-cell subpopulations and T-cell selection, including T-cell receptor-deficient (10,11), major histocompatibility complex class II-deficient (11), and severe combined immunodeficient mice restored with CD45RBHI helper T cells (12,13); human leukocyte antigen (HLA)-B27 rats (14); mice with targeted disruption of cytokine genes, including IL-10 (15), IL-2 (16,17), and transforming growth factor-
(18,19); and mice lacking signaling proteins important in T cells, including 
i2 subunit of G protein (20) or SMAD3 (21). Although these animals have a variety of specific defects in immune function, as noted by Powrie (4), all share a common feature in that, in each, the T-cell-dependent regulatory system that normally protects the gut is disrupted. One implication of these studies is that T lymphocytes play a critical role in the development and maintenance of oral tolerance (5). While direct evidence of the role of these genes in the development of IBD in humans is lacking, there are immunoregulatory features in Crohn's disease and ulcerative colitis, including a decreased ratio of IL-1ra to IL-1 in mucosal biopsy specimens from ulcerative colitis and Crohn's patients (22). IL-1ra is a circulating IL-1 receptor, which, if present at high levels, negatively regulates the effects of IL-1. In addition, some experimental evidence (23) suggests that monocytes from IBD patients may produce less IL-4, a key anti-inflammatory cytokine.
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Ibd IN IL-10-DEFICIENT MICE |
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TopNotesAbstractIntroductionAbnormal Host Immune Responses...Ibd in IL-10-Deficient MiceIL-11 in the Treatment...Relationship of Inflammatory...Future Research DirectionsReferences |
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Mice deficient in IL-10 have been especially useful in understanding the role of inflammatory cytokines and other factors in the development of mucosal inflammation. IL-10 was initially identified as an activity produced by TH2 cells that inhibited the production of cytokines by TH1 cells (24). However, IL-10 has effects on a broad range of immune functions and is a potent suppressor of macrophage activation, inhibiting production of inflammatory cytokines, such as IL-1, IL-6, and TNF-
. Kuhn et al. (15) described the development of mice deficient in IL-10 generated by homologous recombination targeting the IL-10 gene in embryonic stem cells. Surprisingly, these mice developed normal numbers of B and T lymphocytes and demonstrated a normal immune response to T-cell-dependent immunizations. However, these mice developed an abnormal TH1 response to nematode infection with increased production of INF- and IL-5. The animals were also growth retarded and developed a microcytic anemia that was likely caused by iron deficiency. The principal histopathologic finding in anemic and low-weight mice was a chronic enterocolitis involving the entire intestinal tract. The pathologic lesions in the intestine included mucosal inflammation, degeneration of the intestinal mucosa, and marked thickening of the mucosal wall associated with excessive regenerative hyperplasia. Mucosal surfaces demonstrated desquamation of the apical epithelia with superficial erosions and inflammatory exudates. Extensive histiocytic, lymphoid, macrophage, neutrophil, eosinophil, and plasma cell infiltration was seen in the lamina propria and submucosa regions. The duodenum showed the most extensive abnormalities, but changes were seen throughout the gastrointestinal tract. These pathologic changes were attenuated in mice bred in specific-pathogen-free (SPF) conditions, suggesting a role for microbial antigens in the severity or progression of the IBD.
In a subsequent study, Berg et al. (25) demonstrated disease progression that occurred in mice kept in SPF conditions. These studies documented the fact that inflammatory changes first occurred in the cecum and ascending and transverse colon and ultimately involved the rectum and small intestine. Prolonged disease was associated with transmural lesions and increased incidence of adenocarcinomas. Mechanistically, Berg et al. (25) demonstrated increased amounts of inflammatory cytokines (IL-1, TNF-, IL-6, IFN , and NO) produced in colonic cultures of IL-10-deficient mice. Purified CD4+ T cells derived from the colons of these mice also produced substantially more IFN . Treatment of mice with anti-IFN antibodies prevented colitis from developing, and administration of IL-10 substantially reduced colitis, duodenitis, and the incidence of colorectal adenocarcinoma. These studies also demonstrated genetic differences in disease susceptibility, since a marked difference in the development of intestinal lesions was seen in multiple inbred mouse strains. Kullberg et al. (26) more recently demonstrated that IL-10-deficient mice reared in SPF conditions that were experimentally infected with Helicobacter hepaticus developed chronic colitis associated with a TH1 cytokine response (TNF-, IFN , and NO). In this experimental infection with one specific microbe, neutralization of IFN or IL-12 in vivo with antibodies resulted in a substantial reduction in intestinal inflammation. In summary, the data generated from IL-10-deficient mice suggest a key role for proinflammatory cytokines, inheritable factors, and microbial antigens in the development and progression of IBD.
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IL-11 IN THE TREATMENT OF INFLAMMATORY DAMAGE OF THE INTESTINE |
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TopNotesAbstractIntroductionAbnormal Host Immune Responses...Ibd in IL-10-Deficient MiceIL-11 in the Treatment...Relationship of Inflammatory...Future Research DirectionsReferences |
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As noted above, IL-11 is a pleiotropic cytokine of mesenchymal origin. The cloning of the complementary DNA (cDNA) responsible for IL-11 activity followed the development of more than 60 immortalized stromal cell lines from primate bone marrow by using a recombinant retrovirus vector expressing simian virus 40 large T antigen (27). Of these cell lines, one designated PU-34 demonstrated the capacity to generate megakaryocytic cells from human CD34+ cells when used in long-term cultures. Conditioned medium from this cell line was shown to support proliferation of an IL-6-dependent plasmacytoma cell line, T1165, in the presence of excess neutralizing antibodies to IL-6. Because of data suggesting a role for IL-6 in megakaryocyte colony growth in some systems, this activity was further studied. With the use of expression cloning methods and the IL-6-dependent plasmacytoma cell line, an IL-11 cDNA was cloned (along with multiple IL-6 cDNA clones) and was shown to have megakaryocyte colony-forming activity in vitro (28). Subsequently, IL-11 was shown to stimulate the recovery of platelets in vivo after cytoablative therapy (29) and in normal mice (30). Effects on platelet production were seen in a variety of preclinical models and in early-phase trials in humans [for a review, see (31)]. In 1998, the U.S. Food and Drug Administration approved IL-11 (Neumega) as the first pharmacologic agent for the treatment of chemotherapy-induced thrombocytopenia.
Human IL-11 is a 199-amino-acid protein with a molecular weight of approximately 19 kd [reviewed in (32)]. The gene maps to 19q13.3–q13.4 in a region that contains several zinc finger genes and spans 7 kilobases (33). The protein, unlike many cytokines, is not glycosylated and has no cysteine residues or potential N-linked glycosylation sites. The cytokine probably has a structure with a four-helix bundle topology with two receptor-binding sites located in the carboxyl terminus (34). Many mesenchymal cell lines have been shown to express IL-11, whereas IL-11 messenger RNA is abundant in the murine testis, hippocampal neuronal cells, and motor neurons and sympathetic neurons of the spinal cord (35). IL-11 is a member of the IL-6 cytokine superfamily. The receptor for IL-11 contains a common GP130-signaling subunit and a specific chain (36). Binding of IL-11 stimulates receptor dimerization, activation, and phosphorylation of Jak/Stat proteins.
In an effort to develop more severe thrombocytopenia in a mouse model in which to test the stimulatory activity of IL-11, Du et al. (6) treated mice with the combination of total-body irradiation and 5-fluorouracil (5-FU). Mice treated with this combination therapy and IL-11 were noted to survive at significantly (P = .01) higher frequency than control mice. Neither an increase in leukocyte counts nor significant changes in bleeding explained the survival differences. Because deaths occurred rapidly after cytoablative therapy, examination of the gut was undertaken; this analysis demonstrated marked changes in the mucosal architecture. Control mice demonstrated significant (P = .01) shortening of villus length and areas of ulcerations accompanied by enteric bacterial foci in the liver. IL-11 treatment was associated with increased villus length, preserved villus/crypt ratios, and reduced incidence of hepatic bacterial foci. Subsequent studies by many laboratories have demonstrated similar results in multiple models of gut injury, including ischemia (37), burn (38), short gut (39), trinitrobenzene sulfonic acid (40), HLA-B27 rat (41), 5-FU-induced mucositis (42), radiation therapy alone (43), and graft-versus-host disease (GVHD) (44). One study suggests a direct effect on mucosal cells in vivo (45).
Studies on GVHD provide evidence of the mechanisms by which IL-11 may be acting in these varied models. GVHD is a multisystem disease in which donor T cells directed against host antigen(s) mediate inflammation and tissue damage. Common end organs affected in GVHD include skin, gastrointestinal tract, liver, and blood cells (46). Clinical symptoms include exfoliative skin rashes, hepatitis, diarrhea, weight loss, immune-mediated blood cell destruction, and increased incidence of opportunistic infections. Although the specific host antigens that are mediators of GVHD have not been identified, modulation of the incidence and severity of the disease occurs with T-cell depletion of the donor stem cell preparation (46). Hill et al. (44) demonstrated that administration of IL-11 in an animal model of GVHD significantly (P = .05) reduces the incidence and severity of intestinal complications and leads to increased survival of treated mice. These changes in the intestinal mucosa were associated with a substantial reduction in IFN and IL-2 secretion and an increase in IL-4 secretion. The TH2 polarization of the T-cell response also led to decreased IL-12 production in mixed lymphocyte cultures in vitro (44). It is interesting that systemic levels of TNF-, a potent inflammatory cytokine, were significantly (P = .01) reduced by IL-11 treatment. The authors hypothesized that IL-11 treatment reduced GVHD morbidity and mortality by polarization of donor T cells (to TH2 response), protection of the small intestine, and suppression of inflammatory cytokines.
Additional studies have also provided evidence that IL-11 has potent anti-inflammatory effects and may be acting in the gut by modulating macrophage cytokine production. Trepicchio et al. (47) have demonstrated that administration of IL-11 to lipopolysaccharide-treated mice reduced TNF-, IL-1, and IFN levels in vivo. Treatment of isolated macrophages in vitro with IL-11 led to reduced production of these same cytokines and IL-12 p40 and NO. Subsequent studies demonstrated a dose-dependent decrease in IL-12 production by macrophages after combined IFN /Staphylococcus aureus stimulation in vivo. This decrease in expression of IL-12 was caused by transcriptional regulation (48). This transcriptional effect could be due to increased expression of IkB- and I
B- with subsequent decreased nuclear translocation of NF-kB in macrophages (49). Thus, studies support the hypothesis that IL-11 may be beneficial in IBD by a combination of direct effects on enterocyte production/survival and modulation of immune responses, including systemic reduction in inflammatory cytokines.
Early studies in humans have supported the preclinical data presented above. A multicenter, double-masked, placebo-controlled study in 76 patients with IBD demonstrated the expected increase in platelet counts and showed that 42% of IL-11-treated patients had a positive clinical response in terms of IBD symptoms, versus 7% in the placebo group (50). This dose-escalation study showed minimal toxic effects with IL-11 given subcutaneously two times per week. The response was seen at a dose of 16 µg/kg per week. A multicenter, double-masked, placebo-controlled phase II study has been recently reported in abstract form (51). In this study, 148 patients with active disease (Crohn's disease activity index [CDAI] >220) were given placebo versus IL-11 in two schedules (15 µg/kg once a week or 7.5 µg/kg twice a week). Results in the once-a-week group showed a trend toward decreased mean percentage CDAI (32% versus 18% in placebo) and a substantial increase in remission rate (37% versus 16% in placebo, P<.05). Treatment using the twice-a-week schedule was effective but was associated with increased rates of side effects, including headache, edema, and increased platelet counts. These side effects were not noted at any increased frequency in the once-a-week treatment group compared with the placebo group. Thus, IL-11 appears to be both safe and effective in inducing remissions in a subset of patients with active Crohn's disease. On the basis of these early clinical studies, a multi-institutional phase III trial is now under way (Schwertschlag U: personal communication).
The expression of inflammatory cytokines appears to play a critical role in the development and progression of IBD. On the basis of a number of preclinical animal models, in which the expression of these cytokines is modulated, and early human clinical trials, expression of inflammatory cytokines appears to be an important target for the development of novel therapies for IBD and other diseases in which intestinal mucosal damage occurs, such as mucositis and GVHD.
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RELATIONSHIP OF INFLAMMATORY CYTOKINES AND MUCOSAL INJURY IN CANCER |
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TopNotesAbstractIntroductionAbnormal Host Immune Responses...Ibd in IL-10-Deficient MiceIL-11 in the Treatment...Relationship of Inflammatory...Future Research DirectionsReferences |
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The generation of mucositis and bowel injury accompanying chemotherapy and radiation therapy used in cancer treatment continues to be a major source of morbidity for many patients. In addition, these side effects of cancer therapy can frequently have adverse consequences on dose intensity and, therefore, compromise multimodality approaches to the cure of cancer. Mucosal injury is also a striking component of GVHD seen in the postallogeneic stem cell transplant setting, a process that substantially increases morbidity and mortality in those using this therapeutic approach for the treatment of cancer. Although direct cytotoxicity of many chemotherapy agents and radiation to intestinal mucosal cells undoubtedly plays a major role in the development of mucositis and other intestinal complications of these therapies, inflammatory cytokines, as discussed in this article, probably also contribute substantially to the severity and maintenance of injury.
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FUTURE RESEARCH DIRECTIONS |
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TopNotesAbstractIntroductionAbnormal Host Immune Responses...Ibd in IL-10-Deficient MiceIL-11 in the Treatment...Relationship of Inflammatory...Future Research DirectionsReferences |
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The use of transgenic and gene-targeted mice will continue to elucidate important mechanisms of mucosal injury. These studies, therefore, provide logical and relevant targets for future pharmacologic intervention. Future studies are needed to continue to define the basic mechanisms of mucosal cell growth and differentiation but also should aim to translate these findings into patient-focused research in the treatment of IBD, mucositis, and other gastrointestinal complications of cancer therapies
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NOTES |
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D. A. Williams is a patent holder on the use of interleukin 11 (IL-11) in the treatment of gut damage. He receives payments from Children's Hospital, Boston, MA, based on milestones set forth in an IL-11 agreement between Genetics Institute (Cambridge, MA) and Children's Hospital.
I thank Eva Meunier and Sharon Smoot for excellent administrative assistance and Drs. James Keith, Ullrich Schwertschlag, Andrew Dorner, Sandy Goldman, Stephen Sonis, and Steven Clark for many helpful discussions.
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TopNotesAbstractIntroductionAbnormal Host Immune Responses...Ibd in IL-10-Deficient MiceIL-11 in the Treatment...Relationship of Inflammatory...Future Research DirectionsReferences |
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