IL-13 signal transduction in human monocytes: phosphorylation of receptor components, association with Jaks, and phosphorylation/activation of Stats.
Interleukin (IL)-13 regulates monocyte function and is a potent stimulator of 15-lipoxygenase expression. In different cell types, the functional IL-13 receptor complex can be comprised of variable protein components and has not been thoroughly examined in human monocytes. Here, we identify the receptor components and upstream signaling events initiated by IL-13 in primary human blood monocytes. The expression, phosphorylation and associated Jak kinases of the known, variable receptor components, IL-4R(alpha), IL-2Rgammac, IL-13R(alpha)1 and IL-13R(alpha)2, were examined. We determined that IL-4R(alpha) and IL13R(alpha)1 are phosphorylated upon exposure to IL-13. Although IL-2Rgammac is also expressed, it is not phosphorylated upon exposure to IL-13. Evaluation of the presence of IL-13R(alpha)2 failed to reveal significant mRNA or protein expression. Earlier, our laboratory showed that IL-13 induced the phosphorylation of Jak2 and Tyk2 in monocytes and that expression of both Jaks was essential for downstream signaling by IL-13. Here, we report that Jak2 is associated with IL-4R(alpha), and Tyk2 is associated with the IL-13R(alpha)1 component of the IL-13 receptor complex. Additionally, Stat proteins 1alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. Further, the nuclear translocation and DNA binding of each of these Stats were induced by IL-13. These data represent the first complete report of the functional IL-13 receptor complex and early signaling events in human monocytes. This information is critical for understanding the IL-13 response of monocytes in inflammation.
Roy
Biswajit
B
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio 44195, USA.
Bhattacharjee
Ashish
A
Xu
Bo
B
Ford
Dwayne
D
Maizel
Abby L
AL
Cathcart
Martha K
MK
D021581:Active Transport, Cell Nucleus; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D050832:Interferon-Stimulated Gene Factor 3; D018793:Interleukin-13 / Q000494:pharmacology / Q000502:physiology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D053614:Janus Kinase 2; D046911:Macromolecular Substances; D008894:Milk Proteins; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D053660:Receptors, Interleukin-13; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C508181:IL13RA1 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D046911:Macromolecular Substances; D008894:Milk Proteins; D021122:Protein Subunits; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D015375:Receptors, Interleukin-2; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C079868:gamma interferon activation factor; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human