Deficiency in IRAK4 activity attenuates manifestations of murine Lupus.
Interleukin-1 receptor-associated kinase (IRAK) 4 mediates host defense against infections. As an active kinase, IRAK4 elicits full spectra of myeloid differentiation primary response protein (MyD) 88-dependent responses, while kinase-inactive IRAK4 induces a subset of cytokines and negative regulators whose expression is not regulated by mRNA stability. IRAK4 kinase activity is critical for resistance against Streptococcus pneumoniae, but its involvement in autoimmunity is incompletely understood. In this study, we determined the role of IRAK4 kinase activity in murine lupus. Lupus development in BXSB mice expressing the Y chromosome autoimmunity accelerator (Yaa) increased basal and Toll-like receptor (TLR) 4/7-induced phosphorylation of mitogen-activated protein kinases, p65 nuclear factor-κB (NF-κB), enhanced tumor necrosis factor (TNF)-α and C-C motif chemokine ligand (CCL) 5 gene expression in splenic macrophages, but decreased levels of Toll-interacting protein and IRAK-M, without affecting IRAK4 or IRAK1 expression. Mice harboring kinase-inactive IRAK4 on the lupus-prone Yaa background manifested blunted TLR signaling in macrophages and reduced glomerulonephritis, splenomegaly, serum anti-nuclear antibodies, numbers of splenic macrophages, total and TNF-α+ dendritic cells, activated T- and B-lymphocytes, and lower TNF-α expression in macrophages compared with lupus-prone mice with functional IRAK4. Thus, IRAK4 kinase activity contributes to murine lupus and could represent a new therapeutic target.
['Murphy|Michael|M|', 'Pattabiraman|Goutham|G|', 'Manavalan|Tissa T|TT|', 'Medvedev|Andrei E|AE|']
D000818:Animals D015551:Autoimmunity D018946:Chemokine CCL5 D016207:Cytokines D007153:Immunologic Deficiency Syndromes D053592:Interleukin-1 Receptor-Associated Kinases D008181:Lupus Nephritis D008264:Macrophages D051379:Mice D020928:Mitogen-Activated Protein Kinases D016328:NF-kappa B D010766:Phosphorylation D000081207:Primary Immunodeficiency Diseases D015398:Signal Transduction D013154:Spleen D051193:Toll-Like Receptors D014409:Tumor Necrosis Factor-alpha
IRAK4 Autoimmunity Innate Immunity Macrophage Toll-like receptors (TLRs)