IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease.
Both IL-23- and IL-1-mediated signaling pathways play important roles in Th17 cell differentiation, cytokine production, and autoimmune diseases. The IL-1R-associated kinase 4 (IRAK4) is critical for IL-1/TLR signaling. We show here that inactivation of IRAK4 kinase in mice (IRAK4 KI) results in significant resistance to experimental autoimmune encephalomyelitis due to a reduction in infiltrating inflammatory cells into the CNS and reduced Ag-specific CD4(+) T cell-mediated IL-17 production. Adoptive transfer of myelin oligodendrocyte glycoprotein 35-55-specific IRAK4 KI Th17 cells failed to induce experimental autoimmune encephalomyelitis in either wild-type or IRAK4 KI recipient mice, indicating the lack of autoantigen-specific Th17 cell activities in the absence of IRAK4 kinase activity. Furthermore, the absence of IRAK4 kinase activity blocked induction of IL-23R expression, STAT3 activation by IL-23, and Th17 cytokine expression in differentiated Th17 cells. Importantly, blockade of IL-1 signaling by IL-1RA inhibited Th17 differentiation and IL-23-induced cytokine expression in differentiated Th17 cells. The results of these studies demonstrate that IL-1-mediated IRAK4 kinase activity in T cells is essential for induction of IL-23R expression, Th17 differentiation, and autoimmune disease.
Staschke
Kirk A
KA
Eli Lilly and Co., Indianapolis, IN 46285, USA.
Dong
Sucai
S
Saha
Joy
J
Zhao
Jingyong
J
Brooks
Nathan A
NA
Hepburn
Deena L
DL
Xia
Jinqi
J
Gulen
Muhammet F
MF
Kang
Zizhen
Z
Altuntas
Cengiz Z
CZ
Tuohy
Vincent K
VK
Gilmour
Raymond
R
Li
Xiaoxia
X
Na
Songqing
S
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002464:Cell Migration Inhibition / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D055879:Gene Knock-In Techniques; D006023:Glycoproteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D007113:Immunity, Innate / Q000235:genetics; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology
D006023:Glycoproteins; C098680:Il17a protein, mouse; D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse