Mycobacterium tuberculosis lipoarabinomannan-mediated IRAK-M induction negatively regulates Toll-like receptor-dependent interleukin-12 p40 production in macrophages.
Mannose-capped lipoarabinomannans (Man-LAMs) are members of the repertoire of Mycobacterium tuberculosis modulins that the bacillus uses to subvert the host innate immune response. Interleukin-12 (IL-12) production is critical for mounting an effective immune response by the host against M. tuberculosis. We demonstrate that Man-LAM inhibits IL-12 p40 production mediated by subsequent challenge with lipopolysaccharide (LPS). Man-LAM inhibits LPS-induced IL-12 p40 expression in an IL-10-independent manner. It attenuates LPS-induced NF-kappaB-driven luciferase gene expression, suggesting that its effects are likely directly related to inhibition of NF-kappaB. This is probably because of dampening of the Toll-like receptor signaling. Man-LAM inhibits IL-1 receptor-associated kinase (IRAK)-TRAF6 interaction as well as IkappaB-alpha phosphorylation. It directly attenuates nuclear translocation and DNA binding of c-Rel and p50. Man-LAM exerts these effects by inducing the expression of Irak-M, a negative regulator of TLR signaling. Knockdown of Irak-M expression by RNA interference reinstates LPS-induced IL-12 production in Man-LAM-pretreated cells. The fact that Irak-M expression could be elicited by yeast mannan suggested that ligation of the mannose receptor by the mannooligosaccharide caps of LAM was the probable trigger for IRAK-M induction.
Pathak
Sushil Kumar
SK
Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
Basu
Sanchita
S
Bhattacharyya
Asima
A
Pathak
Shresh
S
Kundu
Manikuntala
M
Basu
Joyoti
J
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D020868:Gene Silencing; D017930:Genes, Reporter; D020672:I-kappa B Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D053592:Interleukin-1 Receptor-Associated Kinases; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D008358:Mannose / Q000737:chemistry; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014162:Transfection
D020672:I-kappa B Proteins; D053762:Interleukin-12 Subunit p40; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009844:Oligosaccharides; D021122:Protein Subunits; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; C050016:lipoarabinomannan; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha; D018664:Interleukin-12; D008156:Luciferases; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D008358:Mannose