Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis

Abstract

Complement represents a chief component of innate immunity in host defense. However, excessive complement activation has been involved in the pathogenesis of inflammatory diseases. In this study, we investigated the contribution of complement to intestinal pathology of patients and rodents with inflammatory bowel disease. The expression of complement effectors (C3a and C3) was increased remarkably in inflamed colons of IBD patients compared with those of normal counterparts. In accordance with this, the sustained activation of complement in serum and colon (including elevated C3a and C5a levels, enhanced hemolytic activity, downregulated expression of C5a receptors) was observed, following the establishment of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which peaked at 24 h. Mice pretreated with neutralizing anti-C5a antibodies (À2, 0, and 2 days after TNBS instillation) had significantly reduced weight loss and improved macroscopic/microscopic scores, comparable to the efficacy of prednisolone treatment. Strikingly, treatment with anti-C5a at 24 h after TNBS instillation showed remarkable therapeutic effects, whereas prednisolone did not. The efficacy of anti-C5a administration was associated with decreased release of proinflammatory chemokines and cytokines, inhibition of infiltration of neutrophils into colons, and enhanced Th2 response. These findings suggest a disease-promoting role of complement, particular C5a, in the pathology of TNBS-induced colitis in mice, indicating possible therapeutic potentials for C5a-specific antibody in IBD. The inflammatory bowel diseases (IBDs) encompassing Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of gastrointestinal tract, characterized by dysfunction of mucosal T cells, abnormal cytokine production, cellular inflammation, and ultimately damage to the intestinal lining. 1 Although the etiology of IBD remains unknown, there is circumstantial evidence to link IBD to the mucosal immune system's failure to attenuate immunity to endogenous antigen. 1 In recent years, several animal IBD models have been developed. 2,3 Although the relationship of many of these models to human disease is imperfect, the hapten-induced model of colonic inflammation in which 2,4,6-trinitrobenzene sulfonic acid (TNBS) is delivered intrarectally to BALB/c mice displays human CD-like features, notably predominantly IL-12-driving Th1 activity of the mucosal CD4 þ T-cell population and transmural mononuclear inflammation. 3 More recently, a pathogenic role of IL-23, the cytokine sharing p40 subunits with IL-12, has been evidenced in the development of CD. 4 Deficiency of IL-23-specific subunits (p19) leads to failure of colitis induction in a T-cell transfer model. This effect is attributed to suppression of IL-17 production and Th17 differentiation in the colons. 5 The factors that initiate intestinal pathology of CD and elicit Th1/Th17 immune reaction, however, are still

Downregulation of Hematopoietic MUC1 during Experimental Colitis Increases Tumor-Promoting Myeloid-Derived Suppressor Cells

“…Defa 20 was observed to be similarly up regulated in a mouse model of 1,2 dimethylhydrazine (DMH)-induced colorectal cancer and thought to be associated with tumorigenesis (42). Increased activation of the complement pathway in the post-colitic KO→WT mucosa also parallels studies by others which show elevation of the complement effector protein, C3, in the colon of IBD patients (43). Additionally, activation of the complement pathway is also a potential immune suppressive mechanism which could promote tumor formation in CAC (44).…”

Human colonic epithelial cells detect and respond to C5a via apically expressed C5aR through the ERK pathway

“…Systemic administration of C5aR-specific small interfering RNA is capable of reducing C5aR gene expression in vivo and was shown to prevent ischemia/reperfusion injury of kidney and lung (47,48,57). Blockade of the C5aR demonstrated protective effects in TNBS-induced colitis in rats (55) and using a specific antiserum to block C5a had therapeutic effects on TNBS-induced colitis in mice (11). Although the activation of complement components may be strictly limited under normal conditions in the gut, complement activation most certainly has an impact on diseases of the gastrointestinal tract.…”

Properdin Provides Protection from Citrobacter rodentium–Induced Intestinal Inflammation in a C5a/IL-6–Dependent Manner

“…We showed earlier that PMX205 protects from trinitrobenzene sulfonic acid-and dextran sulfate sodium-induced colitis in rats and mice, respectively (22,44,45), and others had the same outcome using a C5a blocking Ab in mouse trinitrobenzene sulfonic acid colitis (46). This difference from the chemical colitis models may be explained by the different effects of IL-6 on infectious versus noninfectious models; for example, IL-6 is proinflammatory in chemical (47) and T cell-dependent models of colitis (48) but is protective against C. rodentium-induced colonic inflammation (24).…”