Unusual interleukin-4 and -13 signaling in human normal and tumor lung fibroblasts.
IL-4 and IL-13 act on human lung fibroblasts through specific receptors differing in their composition. Indeed, the gammac chain is constitutively expressed in tumor lung myofibroblast but not in normal cells. Here, we have analysed the signal transduction induced by IL-4 and IL-13 in both cell types, in order to better understand the molecular mechanisms underlying tumor stromal development. The IL-4Ralpha chain is constitutively phosphorylated and pre-associated with the JAK1 protein in both cell types. In normal cells, we detected the activation of the classic IRS-2 or JAK1/STAT6 pathways, the phosphorylation of JAK2, while Tyk2 was constitutively phosphorylated and not modified by both cytokines. In addition to these pathways, in lung tumor myofibroblasts, IL-4 and IL-13 induced the phosphorylation of JAK3 and increased the phosphorylation of Tyk2. Interestingly, in both cell types IL-4 and IL-13 triggered an unusual pattern of STAT1 and STAT3 activation. These events probably correspond to a tissue-specific signaling important for the immunoregulatory functions of airways fibroblasts. Indeed, the inflammatory-like pattern of STATs signaling triggered by IL-4 and IL-13 in these cells may favor the homing of inflammatory and/or metastatic cells. In lung myofibroblasts, these properties could be modified through the different pattern of JAK activation.
Doucet
C
C
INSERM U268, H pital Paul Brousse, Villejuif, France.
Jasmin
C
C
Azzarone
B
B
D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D018793:Interleukin-13; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D019948:Receptors, Interleukin-4; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases