Down-Modulation of Pro-Inflammatory Cytokines in Experimental Colitis and in Inflammatory Bowel Disease by a Narrow Spectrum Kinase Inhibitor

BIANCHERI P; CURCIARELLO R; POWELL N; LO, J.W; WALSHE, C; WEBBER, S; KAZUHIRO ITO; GIUFFRIDA, P; DISABATINO, A; CORAZZA GR; GRHAM, L; MACDONALD TT

Vancouver, BC

Congreso; 16th International Congress of Mucosal Immunology; 2013

Society of Mucosal Immunology

Background and Aims: Mitogen-activated protein kinases are crucial regulators of mucosal proinflammatorycytokine expression in both experimental colitis and inflammatory bowel disease (IBD). Weevaluated the effects of a narrow spectrum kinase inhibitor (NSKI-1) on IBD inflamed mucosa and onmouse colitis. Methods: NSKI-1 (1-100ng/ml) or BIRB796 (1μg/ml) was added to biopsies or anti-CD3/anti-CD28-stimulated lamina propria mononuclear cells (LPMCs) isolated from inflamed gut of 19IBD patients. Interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor (TNF)-α were evaluated in 24-hourculture supernatants by ELISA. Colitis was induced in Rag2-/- mice by naïve T cell transfer, and colonicexplants were cultured ex vivo with or without NSKI-1 (1-100ng/ml) and assessed as above for proinflammatorycytokine release. Results: NSKI-1, but not BIRB796, inhibited IL-1β, IL-6, IL-8 and TNF-αproduction by inflamed IBD mucosal explants cultured ex vivo. Furthermore, TNF-α release by anti-CD3/anti-CD28stimulated LPMCs was reduced in a dose-response manner by both NSKI-1 and, lesspotently, BIRB796. NSKI-1 inhibited in a dose-response manner IL-1β, IL-6, TNF-α, interferon (IFN)-γ andIL-17A production by explants of inflamed mouse colon. Conclusions: NSKI-1 showed consistent downregulatoryeffects in both mouse and human ex vivo and in vitro models of intestinal inflammation, andmay be a promising candidate for IBD treatment.