Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor alpha chain 1: redundancy of requirement of tyrosine residue for STAT3 activation.
IL-4 and IL-13 are pleiotropic cytokines whose biological activities overlap with each other. IL-13 receptor alpha chain 1 (IL-13R alpha 1) is necessary for binding to IL-13, and the heterodimer composed of IL-13R alpha 1 and IL-4R alpha chain transduces IL-13 and IL-4 signals; however, the functional mapping of the intracellular domain of IL-13R alpha 1 is not fully understood. In this study, we constructed wild and mutated types of human IL-13R alpha 1, and analyzed IL-4 and IL-13 signals using an IL-13R alpha 1-transfected human B cell line. Expression of IL-13R alpha 1 evoked STAT3 activation by IL-4 and IL-13, and in stimulated human B cells, on which IL-13R alpha 1 was highly expressed, IL-4 and IL-13 induced STAT3 activation. Replacement of the two tyrosine residues completely abolished STAT3 activation, although replacing either tyrosine residue alone retained it. Furthermore, we found that the Box1 region and the C-terminal tail of IL-13R alpha 1 were critical for binding to Tyk2, and activation of Jak1, Tyk2, the insulin receptor substrate-1 and STAT6 respectively. These results suggest that STAT3 activation is involved with IL-4 and IL-13 signals in human B cells along with the activation of STAT6, and that there is a unique sequence in IL-13R alpha 1 to activate STAT3.
Umeshita-Suyama
R
R
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Sugimoto
R
R
Akaiwa
M
M
Arima
K
K
Yu
B
B
Wada
M
M
Kuwano
M
M
Nakajima
K
K
Hamasaki
N
N
Izuhara
K
K
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D018793:Interleukin-13 / Q000378:metabolism / Q000502:physiology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000502:physiology*; D053613:Janus Kinase 1; D008213:Lymphocyte Activation; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053660:Receptors, Interleukin-13; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; C508181:IL13RA1 protein, human; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D010750:Phosphoproteins; D011506:Proteins; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human