Ac2PIM-responsive miR-150 and miR-143 target receptor-interacting protein kinase 2 and transforming growth factor beta-activated kinase 1 to suppress NOD2-induced immunomodulators.

Autor:	Prakhar P; From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and., Holla S; From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and., Ghorpade DS; From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and., Gilleron M; Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS and Université de Toulouse, 31077 Toulouse, France., Puzo G; Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS and Université de Toulouse, 31077 Toulouse, France., Udupa V; From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and., Balaji KN; From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and balaji@mcbl.iisc.ernet.in.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2015 Oct 30; Vol. 290 (44), pp. 26576-86. Date of Electronic Publication: 2015 Sep 21.
DOI:	10.1074/jbc.M115.662817
Abstrakt:	Specific and coordinated regulation of innate immune receptor-driven signaling networks often determines the net outcome of the immune responses. Here, we investigated the cross-regulation of toll-like receptor (TLR)2 and nucleotide-binding oligomerization domain (NOD)2 pathways mediated by Ac2PIM, a tetra-acylated form of mycobacterial cell wall component and muramyl dipeptide (MDP), a peptidoglycan derivative respectively. While Ac2PIM treatment of macrophages compromised their ability to induce NOD2-dependent immunomodulators like cyclooxygenase (COX)-2, suppressor of cytokine signaling (SOCS)-3, and matrix metalloproteinase (MMP)-9, no change in the NOD2-responsive NO, TNF-α, VEGF-A, and IL-12 levels was observed. Further, genome-wide microRNA expression profiling identified Ac2PIM-responsive miR-150 and miR-143 to target NOD2 signaling adaptors, RIP2 and TAK1, respectively. Interestingly, Ac2PIM was found to activate the SRC-FAK-PYK2-CREB cascade via TLR2 to recruit CBP/P300 at the promoters of miR-150 and miR-143 and epigenetically induce their expression. Loss-of-function studies utilizing specific miRNA inhibitors establish that Ac2PIM, via the miRNAs, abrogate NOD2-induced PI3K-PKCδ-MAPK pathway to suppress β-catenin-mediated expression of COX-2, SOCS-3, and MMP-9. Our investigation has thus underscored the negative regulatory role of Ac2PIM-TLR2 signaling on NOD2 pathway which could broaden our understanding on vaccine potential or adjuvant utilities of Ac2PIM and/or MDP. (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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