Proinflammatory properties of IL-4 in the intestinal microenvironment

Abstract

IL-4 is involved in type 2 T helper cell (Th)2-type immune responses and, in some cases, can promote Th1 responses. However, the proinflammatory potential of IL-4 alone is unclear. In this study, we examined the ability of IL-4 to induce colitis after its overexpression in the colon using an adenoviral vector (Ad5) and compared results with those obtained after overexpression of IL-12, a cytokine implicated in several models of colitis. Overexpression of IL-4 or IL-12 caused a fatal colitis within 24 h in 60% of animals and was dose and strain dependent. IL-12-induced colitis was accompanied by the local expression of IFN-gamma and TNF-alpha but not IL-4 mRNA and protein. Conversely, IL-4-induced colitis was accompanied by the local expression of IL-4 and TNF-alpha but not IFN-gamma mRNA and protein. The Ad5-IL4-induced colitis did not persist beyond 3 days and was present in recombinase activation gene-2 (RAG-2)-/- mice but not in STAT6-/- mice. Acute lethal colitis induced by Ad5IL12 was T cell mediated and IFN-gamma receptor (IFN-gamma R) dependent. Furthermore, TNF-alpha was found to be important in the pathogenesis of Ad5IL-4 and Ad5IL-12-induced colitis. Results of this study indicate that IL-4 alone can act as a proinflammatory cytokine in the gut of normal mice, inducing a rapid onset and short-lived colonic injury while maintaining a Th2-type cytokine profile that functions via a local T cell-independent mechanism involving TNF-alpha.

Modulation of mucosal immunity in a murine model of food‐induced intestinal inflammation

“…The high expression of GATA-3, IL-4 and IL-13 corroborated with the hypothesis of the modulation of gut immunity towards a Th2 profile of cytokine production [36][37][38], although other studies had demonstrated mixed systemic Th1/Th2 response to peanut antigens in an oral sensitization model [10]. Future studies will be performed to identify and to measure the cytokines produced by specific antigen-activated cells.…”

Concurrent Infection with an Intestinal Helminth Parasite Impairs Host Resistance to EntericCitrobacter rodentiumand EnhancesCitrobacter-Induced Colitis in Mice

“…Van Kampen et al showed that overexpression of IL-4 (or IL-12) in the colonic mucosa (by gene transfer) induced fatal colitis in healthy mice, whereas STAT 6 KO mice failed to develop colitis (46). In a different murine model system with trinitrobenzenesulfonic acid (TNBS)-induced colitis, the helminth-activated STAT 6 pathway was shown to be required for attenuating TNBS-induced Th1 colitis (11).…”

“…An effect of IL-4 on intestinal epithelial cell function has been reported in H. polygyrus challenged mice by anti-IL-4 MAb treatment, which prevented changes in epithelial function such as increased mucosal permeability and an increased Cl Ϫ secretory response to prostaglandin E 2 (35). Furthermore, overexpression of IL-4 in the colonic mucosa results in the development of severe colitis in mice (46). In line with our observation, it has been shown that IFN-␥-deficient mice expressed an increased level of colonic TNF-␣ and developed an enhanced susceptibility and inflammation (41).…”

Th2 Cytokines Down-Regulate TLR Expression and Function in Human Intestinal Epithelial Cells

“…Murine models of chronic intestinal inflammation underscore the alternative proinflammatory potential of Th2 cytokines within the intestinal microflora, exemplified by the induction of potentially fatal colitis in healthy mice after colonic (but not systemic) adenoviral IL-4 overexpression (41). A mucosal IL-4 predominance within the intestinal microenvironment may play an immunopathogenic role in the development and/or maintenance of both hapten-induced (42) and spontaneous chronic colonic inflammation in mice (43).…”