Proinflammatory properties of IL-4 in the intestinal microenvironment.
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.
Van Kampen
C
C
Intestinal Disease Research Program, McMaster University, Hamilton, ON, Canada L8N 3Z5.
Gauldie
J
J
Collins
S M
SM
D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis / Q000494:pharmacology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007249:Inflammation; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology
D000276:Adjuvants, Immunologic; D016207:Cytokines; D015847:Interleukin-4