ABSTRACT
Although the functional roles of interleukin (IL-)13 in haematopoietic cells are well investigated, those in non-haematopoietic cells remain to be addressed. IL-13 exerts its actions by binding to the IL-13 receptor (IL-13R) on target cells, which is composed of IL-13Ralpha1 and the IL-4 receptor alpha chain (IL-4Ralpha). However, there has been no study of localization of IL-13R in each tissue. To address this question, we generated monoclonal anti-IL-13Ralpha1 antibody, and performed immunohistochemistry using this antibody and anti-IL-4Ralpha antibody. Distribution of these two components was the same in all examined tissues. Staining was positive in keratinocytes, hair follicles, and sebaceous and sweat glands in skin; in ciliated respiratory epithelial cells in nasal tissue; in heart muscle cells; in foveola cells, gastric glands, and the smooth muscle layer in stomach; and in hepatocytes in liver. However, staining was undetectable in brain and bone marrow. Fibroblasts and endothelial cells were stained in some tissues. These results provide clues to elucidate the known pathological roles of IL-13 in atopic dermatitis and allergic rhinitis, as well as its unknown physiological roles.
Subject(s)
Receptors, Interleukin/biosynthesis , Animals , Antibodies, Monoclonal/metabolism , Blotting, Western , DNA, Complementary/metabolism , Endothelium/metabolism , Fibroblasts/metabolism , Gastric Mucosa/metabolism , Hair Follicle/metabolism , HeLa Cells , Hepatocytes/metabolism , Humans , Hybridomas/metabolism , Immunohistochemistry , Interleukin-13 Receptor alpha1 Subunit , Keratinocytes/metabolism , Muscle, Smooth/metabolism , Myocardium/metabolism , Nasal Mucosa/metabolism , Plasmids/metabolism , Precipitin Tests , Receptors, Interleukin/physiology , Receptors, Interleukin-13 , Receptors, Interleukin-4/biosynthesis , Respiratory Mucosa/metabolism , Sebaceous Glands/metabolism , Skin/metabolism , Sweat Glands/metabolism , Tissue DistributionABSTRACT
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.
Subject(s)
DNA-Binding Proteins/metabolism , Interleukin-13/physiology , Interleukin-4/physiology , Receptors, Interleukin/physiology , Signal Transduction/immunology , Trans-Activators/metabolism , Tyrosine/physiology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COS Cells , Cell Line , Enzyme Activation/immunology , HeLa Cells , Humans , Insulin Receptor Substrate Proteins , Interleukin-13/metabolism , Interleukin-13 Receptor alpha1 Subunit , Janus Kinase 1 , Lymphocyte Activation , Phosphoproteins/genetics , Phosphoproteins/physiology , Phosphorylation , Protein-Tyrosine Kinases/metabolism , Proteins/metabolism , Receptors, Interleukin/biosynthesis , Receptors, Interleukin/genetics , Receptors, Interleukin-13 , STAT3 Transcription Factor , STAT6 Transcription Factor , Signal Transduction/genetics , TYK2 Kinase , Trans-Activators/physiology , Transfection , Tumor Cells, Cultured , Tyrosine/metabolismABSTRACT
The prevalence of allergic disease has dramatically increased in recent decades, especially in urban and industrialized areas. Allergic diseases are disorders of the immune system, the results of complex interactions among various genetic and environmental factors. Among them, the important role of interleukin 13 (IL-13), a Th2-type cytokine, has recently emerged in the pathogenesis of bronchial asthma. Based on studies using mice, great attention has been paid to the direct effects of IL-13 on bronchial tissues. In this review, we describe recent advances in understanding the signal transduction mechanism of IL-13, the involvement of IL-13 signal-related genes as genetic factors in the pathogenesis of bronchial asthma, and the expression of IL-13 receptor on bronchial tissues. We describe potential strategies for targeting IL-13 signals to improve allergic states.
