G-protein coupled receptor agonists mediate Neu1 sialidase and matrix metalloproteinase-9 cross-talk to induce transactivation of TOLL-like receptors and cellular signaling

详细信息    查看全文

• 作者：Samar Abdulkhalek ; Merry Guo ; Schammim Ray Amith ; Preethi Jayanth ; Myron R. Szewczuk
• 关键词：GPCR ; G-protein coupled receptor ; TLR ; TOLL-like receptors ; LPS ; endotoxin lipopolysaccharide ; pNF¦ÊB ; NF¦ÊB p65 (Rel A) phosphospecific pS529 ; 4MUNANA ; 2&prime ; -(4-methylumbelliferyl)-¦Á-d-N-acetylneuraminic acid ; poly-IC ; polyinosinic&ndash ; polycytidyli
• 刊名：Cellular Signalling
• 出版年：2012
• 出版时间：November, 2012
• 年：2012
• 卷：24
• 期：11
• 页码：2035-2042
• 全文大小：1060 K

文摘

The mechanism(s) behind GPCR transactivation of TLR receptors independent of TLR ligands is unknown. Here, GPCR agonists bombesin, bradykinin, lysophosphatidic acid (LPA), cholesterol, angiotensin-1 and ©\2, but not thrombin induce Neu1 activity in live macrophage cell lines and primary bone marrow macrophage cells from wild-type (WT) mice but not from Neu1-deficient mice. Using immunocytochemistry and NF¦ÊB-dependent secretory alkaline phosphatase (SEAP) analyses, bombesin induced NF¦ÊB activation in BMC-2 and RAW-blue macrophage cells, which was inhibited by MyD88 homodimerization inhibitor, Tamiflu, galardin, piperazine and anti-MMP-9 antibody. Bombesin receptor, neuromedin B (NMBR), forms a complex with TLR4 and MMP9. Silencing MMP9 mRNA using siRNA transfection of RAW-blue macrophage cells markedly reduced Neu1 activity associated with bombesin-, bradykinin- and LPA-treated cells to the untreated controls. These findings uncover a molecular organizational GPCR signaling platform to potentiate Neu1 and MMP-9 cross-talk on the cell surface that is essential for the transactivation of TLR receptors and subsequent cellular signaling.