IL-1R-Associated Kinase-1 Mediates Protein Kinase Cδ-Induced IL-1β Production in Monocytes

The role of IL-1R-associated kinase (IRAK) 1 and its interaction with protein kinase C (PKC)delta in monocytes to regulate IL-1 beta production has not been reported so far. The present study thus investigates such mechanisms in the THP1 cell line and human monocytes. PMA treatment to THP1 cells induced CD11b, TLR2, TLR4, CD36, IRAK1, IRAK3, and IRAK4 expression, IRAK1 kinase activity, PKC delta and JNK phosphorylation, AP-1 and NF-kappa B activation, and secretory IL-1 beta production. Moreover, PMA-induced IL-1 beta production was significantly reduced in the presence of TLR2, TLR4, and CD11b Abs. Rottlerin, a PKC delta-specific inhibitor, significantly reduced PMA-induced IL-1 beta production as well as CD11b, TLR2 expression, and IRAK1-JNK activation. In PKC delta wild-type overexpressing THP1 cells, IRAK1 kinase activity and IL-1 beta production were significantly augmented, whereas recombinant inactive PKCd and PKCd small interfering RNA significantly inhibited basal and PMA-induced IRAK1 activation and IL-1 beta production. Endogenous PKC delta-IRAK1 interaction was observed in quiescent cells, and this interaction was regulated by PMA. IRAK1/4 inhibitors, their small interfering RNAs, and JNK inhibitor also attenuated PMA-induced IL-1 beta production. NF-kappa B activation inhibitor and SN50 peptide inhibitor, however, failed to affect PMA-induced IL-1 beta production. A similar role of IRAK1 in IL-1 beta production and its regulation by PKC delta was evident in the primary human monocytes, thus signifying the importance of our finding. To our knowledge, the results obtained demonstrate for the first time that IRAK1 and PKCd functionally interact to regulate IL-1 beta production in monocytic cells. A novel mechanism of IL-1 beta production that involves TLR2, CD11b, and the PKC delta/IRAK1/JNK/AP-1 axis is thus being proposed. The Journal of Immunology, 2011, 187: 2632-2645.