NOD2 engagement induces proinflammatory cytokine production, but not apoptosis, in leukocytes isolated from patients with Crohn's disease.

Abstract

BACKGROUND: NOD2/CARD15 is a member of the NACHT-LRR (NLR) family of proteins, which recognize the muramyl dipeptide motif from bacterial peptidoglycans. NOD2 has been shown to be involved in the pathogenesis of Crohn's disease. NLR proteins modulate inflammation and apoptosis, and several studies have implicated NOD2 in the induction of cytokines and inflammatory reactions. However, only scarce data are available regarding its role in apoptosis. DONORS AND METHODS: Neutrophils and lymphocytes isolated from the blood from four Crohn's disease patients homozygous for the loss-of-function 3020insC NOD2 mutation were examined for spontaneous and anisomycin-induced apoptosis. They were compared with cells from healthy controls and Crohn's disease patients bearing the wild-type NOD2 allele. Cytokine production after stimulation of mononuclear cells (MNCs) with muramyl dipeptide was assessed by specific immunoassays. RESULTS: We observed that MNCs isolated from the blood of patients with Crohn's disease bearing the loss of function mutation in NOD2 displayed defective muramyl dipeptide-induced cytokine responses, but both granulocytes and lymphocytes from the same donors displayed normal apoptosis. CONCLUSIONS: NOD2 engagement by MDP mainly triggers cytokine activation and inflammatory reactions, but has negligible effects on cell apoptosis.