Differential regulation and role of interleukin-1 receptor associated kinase-M in innate immunity signaling.
Toll-like-receptor mediated signaling is finely regulated by a complex intracellular protein network including the interleukin-1 receptor associate kinases (IRAKs). IRAK-4, 1, and 2 may positively regulate innate immunity signaling through the activation of various downstream kinases such as MAPKs. In contrast, IRAK-M plays an inhibitory role through unknown mechanism. In this report, we show that IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. Furthermore, using bone marrow derived macrophages (BMDM) from wild type, IRAK1(-/-), and IRAK-M(-/-) mice, we have herein demonstrated that IRAK-M selectively attenuates bacterial lipopeptide Pam(3)CSK(4)-induced p38 activation, but not ERK or JNK. IRAK1(-/-) and IRAK-M(-/-)BMDM display distinct activation profile of various MAP kinases upon Pam(3)CSK(4) challenge, indicating that IRAK-M exerts its inhibitory effect through an IRAK1 independent pathway. Pam(3)CSK(4) challenge leads to rapid decrease of MKP-1 protein level in IRAK-M(-/-)BMDM as well as THP-1 cells with decreased IRAK-M expression through siRNA interference. Our findings indicate that IRAK-M selectively attenuates p38 activation and inhibits innate immunity through stabilizing MKP-1.
Su
Jianmin
J
The Laboratory of Innate Immunity and Inflammation, Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Xie
Qifa
Q
Wilson
Ingred
I
Li
Liwu
L
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D055666:Lipopeptides; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018448:Models, Immunological; D010455:Peptides / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010455:Peptides; C507768:IRAK1 protein, human; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases