IRAK inhibitor 4

IRAK inhibitor 4 is an interleukin-1 receptor associated kinase 4(IRAK4) inhibitor. In Vitro: Lack of IRAK-4 impairs the production of proinflammatory mediators by macrophages and DCs in response to?M. bovis?and?M. tuberculosis. IRAK-4^-/- cells stimulated with E. coli LPS display delayed activation kinetics of all signaling proteins analyzed, and exhibit dramatically reduced p65 phosphorylation^[1]. IRAK1/4 (20 μM) has an inhibitory effect on LPS mediated IL-6 production. IRAK1/4 inhibitor do not decrease p38 phosphorylation in AMs. Combination of IRAK1/4 and Rip2 inhibitors inhibits TLR2-mediated cytokine production in sarcoidosis PBMCs and AMs^[2]. IRAK4 is overexpressed and activated in T-ALL. IRAK4 mRNA level is elevated in T-ALL cells from patients compared with the levels detected in thymic T cells or T cells from peripheral blood^[3]. In Vivo: IRAK-4^-/-?mice exhibit a greatly reduced survival rate following aerosol infection compared with IRAK-4^+/+?or IRAK-4^+/-?mice. IRAK-4^-/- mice show increased bacterial burden in all organs at 15, 30, and 60 d postinfection^[1]. MCL1, but not BCL-xL, overrides the therapeutic effects of combinatorial IRAK1/4 inhibitor and ABT-737 therapy in vivo^[3].