title: G-protein coupled receptor agonists mediate Neu1 sialidase and matrix metalloproteinase-9 cross-talk to induce transactivation of TOLL-like receptors and cellular signaling.
abstract: 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 NFκB-dependent secretory alkaline phosphatase (SEAP) analyses, bombesin induced NFκB 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.
authors: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario, Canada. samarma@hotmail.com
authors: Samar
authors: S
authors: Abdulkhalek
authors: Merry
authors: M
authors: Guo
authors: Schammim Ray
authors: SR
authors: Amith
authors: Preethi
authors: P
authors: Jayanth
authors: Myron R
authors: MR
authors: Szewczuk
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001839:Bombesin / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D008246:Lysophospholipids / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009439:Neuraminidase / Q000378:metabolism*; D015287:Neurokinin B / Q000031:analogs & derivatives / Q000378:metabolism; D053139:Oseltamivir / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018004:Receptors, Bombesin / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D008246:Lysophospholipids; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018004:Receptors, Bombesin; D043562:Receptors, G-Protein-Coupled; D051193:Toll-Like Receptors; D014665:Vasodilator Agents; D053139:Oseltamivir; D015287:Neurokinin B; C038393:neuromedin B; C110128:Neu1 protein, mouse; D009439:Neuraminidase; D020780:Matrix Metalloproteinase 9; C032881:lysophosphatidic acid; D001839:Bombesin; D001920:Bradykinin