Curcumin inhibits interferon-γ signaling in colonic epithelial cells.
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-γ, 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-γ signaling in human and mouse colonocytes. Curcumin inhibited IFN-γ-induced gene transcription, including CII-TA, MHC-II genes (HLA-DRα, HLA-DPα1, HLA-DRβ1), 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 IFNγRα followed by lysosomal fusion and degradation. In summary, curcumin acts as an IFN-γ 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.
Department of Pediatrics, Steele Children's Research Center, Warsaw, Poland.
Monica T
MT
Midura-Kiela
Vijayababu M
VM
Radhakrishnan
Claire B
CB
Larmonier
Daniel
D
Laubitz
Fayez K
FK
Ghishan
Pawel R
PR
Kiela
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D018925:Chemokines / Q000187:drug effects; D003106:Colon / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology; D053613:Janus Kinase 1 / Q000378:metabolism; D008285:Major Histocompatibility Complex; D051379:Mice; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018925:Chemokines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D003474:Curcumin