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 Pam3CSK4 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 Pam3CSK4-induced p38 activation, but not ERK or JNK. IRAK1−/− and IRAK-M−/−BMDM display distinct activation profile of various MAP kinases upon Pam3CSK4 challenge, indicating that IRAK-M exerts its inhibitory effect through an IRAK1 independent pathway. Pam3CSK4 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.