Mechanism of inhibition of eosinophil activation by transforming growth factor-beta. Inhibition of Lyn, MAP, Jak2 kinases and STAT1 nuclear factor.
The activation of eosinophils by IL-5 plays a crucial role in the pathogenesis of allergic and parasitic disorders. IL-5 has recently been shown to activate Lyn and Jak2 tyrosine kinases, MAP kinases, and STAT1 nuclear factor. We have previously reported that TGF-beta blocks the IL-5-induced activation of eosinophils. In this study, we investigated the effect of TGF-beta on the IL-5-induced signaling molecules in eosinophils. Purified eosinophils from mildly allergic patients were preincubated with TGF-beta and then stimulated with IL-5. The cell lysates were then immunoprecipitated and blotted with antiphosphotyrosine Abs. The activity of the kinases was further studied in the immune-complex kinase assay. We found that TGF-beta inhibited the tyrosine phosphorylation of multiple proteins in eosinophils. The identity of some of the proteins was established by immunoprecipitation. We found that TGF-beta inhibited tyrosine phosphorylation of Lyn, Jak2, and a 44-kDa MAP kinase. In further experiments, it blocked the activation of the above kinases as determined by immune-complex kinase assay. TGF-beta also inhibited phosphorylation of the STAT1 (p91) nuclear protein in eosinophils. We believe that the inhibition of Lyn, Jak2, MAP kinase, and the STAT1 nuclear protein may underlie the inhibitory activity of TGF-beta on eosinophils.
Pazdrak
K
K
University of Texas Medical Branch, Department of Internal Medicine, Galveston 77555, USA.
Justement
L
L
Alam
R
R
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D004285:Dogs; D004804:Eosinophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects
D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases