| First Author | Zhang Y | Year | 2009 |
| Journal | J Immunol | Volume | 182 |
| Issue | 1 | Pages | 554-62 |
| PubMed ID | 19109188 | Mgi Jnum | J:142887 |
| Mgi Id | MGI:3822384 | Doi | 10.4049/jimmunol.182.1.554 |
| Citation | Zhang Y, et al. (2009) Immune complex/Ig negatively regulate TLR4-triggered inflammatory response in macrophages through Fc gammaRIIb-dependent PGE2 production. J Immunol 182(1):554-62 |
| abstractText | Excessive activation of TLR may induce endotoxin shock and inflammatory diseases, so the negative regulation of TLR-triggered inflammatory response attracts much attention. Nonpathogenic immune complex (IC) and Ig (IC/Ig) have been shown to play important roles in the regulation of immune responses and to be therapeutic in some kinds of autoimmune diseases. However, the role of IC/Ig in the regulation of TLR-triggered inflammatory responses and the underlying mechanisms remain to be fully understood. In this study we demonstrate that IC/Ig can significantly inhibit LPS-induced secretion of TNF-alpha and IL-6 from macrophages by preferentially inducing PGE(2). Pretreatment of mice with IC can protect wild-type mice, but not Fc gammaRIIb(-/-) mice, from lethal endotoxin shock, and significantly reduce the levels of serum TNF-alpha and IL-6 in wild-type mice but not in Fc gammaR IIb(-/-) mice. Furthermore, blockade of PGE(2) by celecoxib restores LPS-induced production of TNF-alpha and IL-6 in the presence of IC both in vitro and in vivo. Accordingly, blockade of PGE(2) production in vivo results in the increased sensitivity of IC-pretreated mice to lethal endotoxin shock. Therefore, IC/Ig can negatively regulate TLR4-triggered inflammatory response in macrophages through Fc gammaRIIb-dependent PGE(2). In addition, our results suggest that down-regulation of NF-kappaB activation and TLR4 expression but activation of protein kinase A pathway in macrophages by IC/Ig contribute to the negative regulatory process. Thus we provide new manner for the immune regulation and mechanistic explanation for nonpathogenic IC/Ig in the treatment of inflammatory or autoimmune diseases. |
