Carbonic Anhydrase III Has Potential as a Biomarker for Experimental Colitis and Functions as an Immune Regulator by Inhibiting Inflammatory Cytokine Secretion.

Abstract

Simple SummaryThe mechanism underlying the onset of ulcerative colitis (UC) has not yet been elucidated in detail. Unknown components in colorectal tissue may be important risk factors to elucidate the cause of UC; however, they have not been highlighted as targets. To identify key factors, rats with dextran sulfate sodium-induced experimental colitis were used. The level of carbonic anhydrase III was significantly decreased in both the serum and colon tissues of these UC rats. Upon stimulation of peritoneal macrophages (MΦ) with lipopolysaccharide, the intracellular concentration of carbonic anhydrase III significantly decreased, while the secretion of pro-inflammatory cytokines from MΦ treated with an anti-carbonic anhydrase III antibody was negatively regulated. In conclusion, carbonic anhydrase III may be a novel regulator of experimental colitis in rats.Ulcerative colitis (UC) is characterized by chronic inflammation of the large intestine, repeated remissions, and symptom relapses. Although unknown components in colonic regions are deeply involved in the pathogenesis of UC, the causes of UC development and aggravation have not yet been elucidated in detail. To identify key factors, we investigated the changes in protein components in the large intestine of rats with dextran sulfate sodium-induced experimental colitis (UCR). The components that differed in their concentration between normal rats (WT) and UCR were carefully investigated by electrophoretic separation and mass spectrometry. Based on these results, seven proteins with different expression levels between the WT and UCR were observed. Among them, we focused on carbonic anhydrase III (CA-III) in the pathogenesis of UC. CA-III concentrations in the colon tissue and serum were quantitatively measured using an enzyme-linked immunosorbent assay (ELISA) and real-time PCR, and the levels significantly decreased in both the colon tissue and serum of UCR with the aggravation of experimental UC. In an in vitro assay, CA-III function in peritoneal macrophages (MΦ) from rats was investigated. Upon stimulation of MΦ with lipopolysaccharide (LPS), the CA-III concentration significantly decreased in the cytoplasm of these cells. MΦ treated with an anti-CAIII antibody followed by stimulation with LPS actively secreted inflammatory cytokines, particularly interleukin-6 and tumor necrosis factor-α. Therefore, CA-III in MΦ appears to be an immune regulator that suppresses the secretion of inflammatory cytokines.