Reciprocal regulation of protein arginine deiminase 2 and 4 expression in the colonic mucosa of ulcerative colitis

Neutrophils express protein arginine deiminase (PAD)2 and PAD4, both of which mediate the citrullination of target proteins to induce production of neutrophil extracellular traps (NETs). Although PAD-dependent NETs trigger inflammatory bowel disease, the mechanisms governing the expression of PAD2 and PAD4 are poorly understood. In this study, we tried to clarify expression mechanisms of PAD2 and PAD4 in the colonic mucosa of patients with ulcerative colitis (UC) and Crohn's disease (CD). Administration of CI-amidine, a pan PAD-inhibitor, attenuated the development of dextran sodium sulfate-induced colitis, the effects of which were accompanied by reduced IL-6 and TNF-a production by colonic lamina propria mononuclear cells upon exposure to Toll-like receptor ligands. The mRNA expression of colonic PAD2 and PAD4 was negatively and positively correlated with disease activity and pro -inflammatory cytokine responses in patients with UC, respectively. Reciprocal regulation of PAD2 and PAD4 mRNA expression was observed in the colonic mucosa of UC patients, but not in those of CD patients. PAD4 mRNA expression was correlated with disease activity and pro-inflammatory cytokine responses in patients with CD. Collectively, these data suggest that reciprocal regulation of PAD2 and PAD4 expression is associated with disease activity in UC patients.