Mechanisms for the anti-inflammatory effects of adiponectin in macrophages
Article first published online: 12 MAR 2008
© 2007 The Authors
Journal of Gastroenterology and Hepatology
Special Issue: 2nd International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Kobe, Japan
Volume 23, Issue Supplement s1, pages S50–S53, March 2008
How to Cite
Huang, H., Park, P.-H., McMullen, M. R. and Nagy, L. E. (2008), Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. Journal of Gastroenterology and Hepatology, 23: S50–S53. doi: 10.1111/j.1440-1746.2007.05284.x
- Issue published online: 12 MAR 2008
- Article first published online: 12 MAR 2008
- Accepted for publication 1 October 2007.
- alcoholic liver disease;
Adiponectin is an adipokine with potent anti-inflammatory properties. The development of alcoholic liver disease is thought to involve increased pro-inflammatory activity, mediated in part by the activation of hepatic macrophages (Kupffer cells). Chronic ethanol feeding sensitizes hepatic macrophages to activation by lipopolysaccharide (LPS), leading to increased production of reactive oxygen species and tumor necrosis factor-α (TNF-α). Adiponectin can normalize Toll-like receptor-4 (TLR-4) mediated signaling in hepatic macrophages after ethanol feeding, likely contributing to the hepatoprotective effect of adiponectin in the progression of alcoholic liver disease. However, the mechanisms by which adiponectin suppress TLR-4 mediated responses are not well understood. Using the macrophage-like cell line, RAW264.7, we have investigated the molecular mechanisms by which adiponectin suppresses LPS-stimulated TNF-α production. Globular adiponectin (gAcrp)-mediated desensitization of LPS-stimulated responses in RAW264.7 macrophages was dependent on the production of the anti-inflammatory cytokine interleukin (IL)-10. gAcrp initially increased TNF-α expression in RAW264.7 macrophages; this TNF-α then contributed to increased expression of IL-10. This initial gAcrp-mediated increase in TNF-α production by macrophages was mediated via activation of ERK1/2Egr-1 and nuclear factor (NF)-κB-dependent mechanisms. gAcrp-stimulated IL-10 expression was also dependent on the phosphorylation of cAMP response element-binding protein and the cAMP response element in the IL-10 promoter. In summary, these studies reveal a complex, integrated response of macrophages to gAcrp. gAcrp initially activated signaling pathways considered to be pro-inflammatory, with a subsequent increase in the expression of the potent, anti-inflammatory cytokine, IL-10. Increased IL-10 expression was ultimately required for the suppression of TLR4-mediated signaling by gAcrp.