Curcumin inhibits interferon-gamma signaling in colonic epithelial cells

Midura-Kiela MT, Radhakrishnan VM, Larmonier CB, Laubitz D, Ghishan FK, Kiela PR. Curcumin inhibits interferon-gamma signaling in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 302: G85-G96, 2012. First published October 28, 2011; doi:10.1152/ajpgi.00275.2011.-Curcumin (diferulolylmethane) is an anti-inflammatory phenolic compound found effective in preclinical models of inflammatory bowel diseases (IBD) and in ulcerative colitis patients. Pharmacokinetics of curcumin and its poor systemic bioavailability suggest that it targets preferentially intestinal epithelial cells. The intestinal epithelium, an essential component of the gut innate defense mechanisms, is profoundly affected by IFN-gamma, which can disrupt the epithelial barrier function, prevent epithelial cell migration and wound healing, and prime epithelial cells to express major histocompatibility complex class II (MHC-II) molecules and to serve as nonprofessional antigen-presenting cells. In this report we demonstrate that curcumin inhibits IFN-gamma signaling in human and mouse colonocytes. Curcumin inhibited IFN-gamma-induced gene transcription, including CII-TA, MHC-II genes (HLA-DR alpha, HLA-DP alpha 1, HLA-DR beta 1), and T cell chemokines (CXCL9, 10, and 11). Acutely, curcumin inhibited Stat1 binding to the GAS cis-element, prevented Stat1 nuclear translocation, and reduced Jak1 phosphorylation and phosphorylation of Stat1 at Tyr(701). Longer exposure to curcumin led to endocytic internalization of IFN gamma R alpha followed by lysosomal fusion and degradation. In summary, curcumin acts as an IFN-gamma signaling inhibitor in colonocytes with biphasic mechanisms of action, a phenomenon that may partially account for the beneficial effects of curcumin in experimental colitis and in human IBD.