title: Hck is a key regulator of gene expression in alternatively activated human monocytes.
abstract: IL-13 is a Th2 cytokine that promotes alternative activation (M2 polarization) in primary human monocytes. Our studies have characterized the functional IL-13 receptor complex and the downstream signaling events in response to IL-13 stimulation in alternatively activated monocytes/macrophages. In this report, we present evidence that IL-13 induces the activation of a Src family tyrosine kinase, which is required for IL-13 induction of M2 gene expression, including 15-lipoxygenase (15-LO). Our data show that Src kinase activity regulates IL-13-induced p38 MAPK tyrosine phosphorylation via the upstream kinases MKK3 or MKK6. Our findings also reveal that the IL-13 receptor-associated tyrosine kinase Jak2 is required for the activation of both Src kinase as well as p38 MAPK. Further, we found that Src tyrosine kinase-mediated activation of p38 MAPK is required for Stat1 and Stat3 serine 727 phosphorylation in alternatively activated monocytes/macrophages. Additional studies identify Hck as the specific Src family member, stimulated by IL-13 and involved in regulating both p38 MAPK activation and p38 MAPK-mediated 15-LO expression. Finally we show that the Hck regulates the expression of other alternative state (M2)-specific genes (Mannose receptor, MAO-A, and CD36) and therefore conclude that Hck acts as a key regulator controlling gene expression in alternatively activated monocytes/macrophages.
authors: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA. bhattaa@ccf.org
authors: Ashish
authors: A
authors: Bhattacharjee
authors: Srabani
authors: S
authors: Pal
authors: Gerald M
authors: GM
authors: Feldman
authors: Martha K
authors: MK
authors: Cathcart
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis; D018955:CD36 Antigens / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis; D053614:Janus Kinase 2 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008262:Macrophage Activation / Q000502:physiology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051572:Proto-Oncogene Proteins c-hck / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D053660:Receptors, Interleukin-13 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D018793:Interleukin-13; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D053660:Receptors, Interleukin-13; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D001093:Arachidonate 15-Lipoxygenase; D008995:Monoamine Oxidase; C496631:HCK protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051572:Proto-Oncogene Proteins c-hck; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human