Abstract
Interleukin (IL)-13 is a signature cytokine of type 2 inflammation important for the pathogenesis of various diseases, including allergic diseases. Signal transducer and activator of transcription (STAT) 6 is a critical transcriptional factor for the IL-13 signals; however, it remains unknown how expression of the IL-13-induced genes is differentiated by the transcriptional machineries. In this study, we identified IL-13-induced transcriptional factors in lung fibroblasts using DNA microarrays in which SOX11 was included. Knockdown of SOX11 down-regulated expression of periostin and CCL26, both of which are known to be downstream molecules of IL-13, whereas enforced expression of SOX11 together with IL-13 stimulation enhanced expression of periostin. Moreover, we found that in DNA microarrays combining IL-13 induction and SOX11 knockdown there exist both SOX11-dependent and -independent molecules in IL-13-inducible molecules. In the former, many inflammation-related and fibrosis-related molecules, including periostin and CCL26, are involved. These results suggest that SOX11 acts as a trans-acting transcriptional factor downstream of STAT6 and that in lung fibroblasts the IL-13 signals are hierarchically controlled by STAT6 and SOX11.
Highlights
Interleukin (IL)-13 is a signature cytokine of type 2 inflammation important for the pathogenesis of various diseases, including allergic diseases
We found that in DNA microarrays combining IL-13 induction and SOX11 knockdown there exist both SOX11-dependent and -independent molecules in IL-13–inducible molecules. In the former, many inflammation-related and fibrosis-related molecules, including periostin and CCL26, are involved. These results suggest that SOX11 acts as a trans-acting transcriptional factor downstream of STAT6 and that in lung fibroblasts the IL-13 signals are hierarchically controlled by STAT6 and SOX11
The former involves many inflammation-related and fibrosisrelated molecules
Summary
It had already been established that STAT6 plays a critical role in IL-13 signaling [12, 13]. Cycloheximide significantly decreased the expression of all of these IL-13–inducible genes (Fig. 2C), there was still induction of these genes by IL-13 These results suggest that in lung fibroblasts a transacting transcriptional mechanism through STAT6 is involved in the IL-13–mediated expression of periostin, CCL26, and SOCS1. SOX11 was not coimmunoprecipitated with STAT6, excluding the possibility that these two molecules act by forming a heterodimer (data not shown) These results reinforce the role of SOX11 in the trans-regulation mechanism of periostin, indicating that some transcriptional or post-translational modification induced by IL-13 would be required for this mechanism. The finding that knockdown of SOX11 down-regulated IL-13–induced expression of periostin and CCL26 but not of SOCS1 suggested that there would be two groups in IL-13– induced genes in lung fibroblasts: SOX11-dependent and -independent genes To differentiate these two groups, we submitted four groups of genes from NHLFs, with or without stimulation. IL-13 Treatment - - + + + + + Nuclear extract - + + + + + + Labeled probe (Wild-type) + + + + + + Excess unlabeled probe (Wild-type) - - - + - - Anti-STAT6 antibody - - - - + - Control IgG antibody - - - - - + -
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