The IL-6 trans-signaling-STAT3 pathway mediates ECM and cellular proliferation in fibroblasts from hypertrophic scar

Sutapa Ray, Xiaoxi Ju, Hong Sun, Celeste C Finnerty, David N Herndon, Allan R Brasier, Sutapa Ray, Xiaoxi Ju, Hong Sun, Celeste C Finnerty, David N Herndon, Allan R Brasier

Abstract

The molecular mechanisms behind the pathogenesis of postburn hypertrophic scar (HS) remain unclear. Here, we investigate the role of the IL-6 trans-signaling-signal transducer and activator of transcription (STAT)3 pathway in HS fibroblasts (HSFs) derived from post-burn HS skin. HSF showed increased Tyr 705 STAT3 phosphorylation compared with normal fibroblast (NF) after IL-6•IL-6Rα stimulation by immunoassays. The endogenous STAT3 target gene, SOCS3, was upregulated in HSFs and showed increased STAT3 binding on its promoter relative to NFs in a chromatin immunoprecipitation assay. We observed that the cell-surface signaling transducer glycoprotein 130 is upregulated in HSFs by quantitative real-time reverse-transcriptase-PCR and flow cytometry. The production of excessive extracellular matrix (ECM), including the expression of alpha2 (1) procollagen (Col1A2) and fibronectin 1 (FN), was seen in HSFs. A STAT3 peptide inhibitor abrogated FN and Col1A2 gene expression in HSFs indicating involvement of STAT3 in ECM production. The cellular proliferation markers Cyclin D1, Bcl-Xl, and c-Myc were also upregulated in HSF, and knockdown of STAT3 by small interfering RNA attenuated c-Myc expression indicating the essential role of STAT3 in fibroblast proliferation. Taken together, our results suggest that the IL-6 trans-signaling-STAT3 pathway may have an integral role in HS pathogenesis, and disruption of this pathway could be a potential therapeutic strategy for the treatment of post-burn HS.

Trial registration: ClinicalTrials.gov NCT00675714.

Conflict of interest statement

CONFLICT OF INTERSEST

The authors state no conflict of interest.

Figures

Figure 1
Figure 1
(a) Immunohistochemical analysis of phospho-STAT3 (Tyr 705) expression in burned HSskin. ‘A-F’ and G are HS skin stained with anti-phosphoTyr705-STAT3 Ab and control IgG respectively. Panel H-I are normal skin stained with anti-phosphoTyr705-STAT3 Ab. Arrowheads (D-F) show the strong nuclear staining for activated STAT3. A-C, G-H and D-F, I are X10 and X20 magnifications respectively, scale bar: 10µm. (b) Intensity of nuclear staining in the dermis of HS (n=10) and normal skin (n=5) (MetaMorph 7.3). *, p<0.01. (c) Western Immunoblot analysis of phospho-STAT3 (Tyr 705) in HSFs. WCE of NF and HSF were fractionated and Western immunoblot analysis with phospho-STAT3 (Tyr 705) Ab is shown. The numbers at the bottom of the lane indicate the fold induction. β-actin blot (lower panel) shows loading control.
Figure 1
Figure 1
(a) Immunohistochemical analysis of phospho-STAT3 (Tyr 705) expression in burned HSskin. ‘A-F’ and G are HS skin stained with anti-phosphoTyr705-STAT3 Ab and control IgG respectively. Panel H-I are normal skin stained with anti-phosphoTyr705-STAT3 Ab. Arrowheads (D-F) show the strong nuclear staining for activated STAT3. A-C, G-H and D-F, I are X10 and X20 magnifications respectively, scale bar: 10µm. (b) Intensity of nuclear staining in the dermis of HS (n=10) and normal skin (n=5) (MetaMorph 7.3). *, p<0.01. (c) Western Immunoblot analysis of phospho-STAT3 (Tyr 705) in HSFs. WCE of NF and HSF were fractionated and Western immunoblot analysis with phospho-STAT3 (Tyr 705) Ab is shown. The numbers at the bottom of the lane indicate the fold induction. β-actin blot (lower panel) shows loading control.
Figure 1
Figure 1
(a) Immunohistochemical analysis of phospho-STAT3 (Tyr 705) expression in burned HSskin. ‘A-F’ and G are HS skin stained with anti-phosphoTyr705-STAT3 Ab and control IgG respectively. Panel H-I are normal skin stained with anti-phosphoTyr705-STAT3 Ab. Arrowheads (D-F) show the strong nuclear staining for activated STAT3. A-C, G-H and D-F, I are X10 and X20 magnifications respectively, scale bar: 10µm. (b) Intensity of nuclear staining in the dermis of HS (n=10) and normal skin (n=5) (MetaMorph 7.3). *, p<0.01. (c) Western Immunoblot analysis of phospho-STAT3 (Tyr 705) in HSFs. WCE of NF and HSF were fractionated and Western immunoblot analysis with phospho-STAT3 (Tyr 705) Ab is shown. The numbers at the bottom of the lane indicate the fold induction. β-actin blot (lower panel) shows loading control.
Figure 2
Figure 2
(a) Activation of IL-6 trans-signaling in HSF. NF and HSF cells were treated with IL-6•sIL-6Rα (8ng/ml •25ng/ml) for 30 minutes, or left untreated. Total cellular RNA was subjected to Q-RT-PCR for hSOCS3 transcript. Shown is fold change mRNA expression relative to GAPDH. Data represents mean±SD, *, p<0.01. (b) Inhibition of phospho-STAT3 with STAT3 siRNA. NFs and HSFs were transfected with either control or STAT3 siRNA. 72 hours after transfection, cells were stimulated as above and WCE were measured for phosphoTry705-STAT3 by immunoassay (Bio-Rad). Shown is the representative fluorescence intensity of phospho-STAT3 relative to total protein. (c) Inhibition of hSOCS3 gene with STAT3 silencing. Cells were treated as in (b) and total cellular RNA was subjected to Q-RT-PCR for hSOCS3 expression relative to GAPDH. *, p<0.05.
Figure 2
Figure 2
(a) Activation of IL-6 trans-signaling in HSF. NF and HSF cells were treated with IL-6•sIL-6Rα (8ng/ml •25ng/ml) for 30 minutes, or left untreated. Total cellular RNA was subjected to Q-RT-PCR for hSOCS3 transcript. Shown is fold change mRNA expression relative to GAPDH. Data represents mean±SD, *, p<0.01. (b) Inhibition of phospho-STAT3 with STAT3 siRNA. NFs and HSFs were transfected with either control or STAT3 siRNA. 72 hours after transfection, cells were stimulated as above and WCE were measured for phosphoTry705-STAT3 by immunoassay (Bio-Rad). Shown is the representative fluorescence intensity of phospho-STAT3 relative to total protein. (c) Inhibition of hSOCS3 gene with STAT3 silencing. Cells were treated as in (b) and total cellular RNA was subjected to Q-RT-PCR for hSOCS3 expression relative to GAPDH. *, p<0.05.
Figure 2
Figure 2
(a) Activation of IL-6 trans-signaling in HSF. NF and HSF cells were treated with IL-6•sIL-6Rα (8ng/ml •25ng/ml) for 30 minutes, or left untreated. Total cellular RNA was subjected to Q-RT-PCR for hSOCS3 transcript. Shown is fold change mRNA expression relative to GAPDH. Data represents mean±SD, *, p<0.01. (b) Inhibition of phospho-STAT3 with STAT3 siRNA. NFs and HSFs were transfected with either control or STAT3 siRNA. 72 hours after transfection, cells were stimulated as above and WCE were measured for phosphoTry705-STAT3 by immunoassay (Bio-Rad). Shown is the representative fluorescence intensity of phospho-STAT3 relative to total protein. (c) Inhibition of hSOCS3 gene with STAT3 silencing. Cells were treated as in (b) and total cellular RNA was subjected to Q-RT-PCR for hSOCS3 expression relative to GAPDH. *, p<0.05.
Figure 3
Figure 3
hSOCS3 promoter occupancy of STAT3 in HSF and NF. Protein-DNA crosslinked extracts of IL-6•sIL-6Rα (8ng/ml •25ng/ml) stimulated NF and HSF cells were immunoprecipitated with IgG or anti-STAT3 Ab. SOCS3 promoter occupancy of STAT3 were detected by two step ChIP assays as described in the method. Shown is the fold change in quantitative-genomic PCR (Q-gPCR) normalized to input DNA. *, p<0.01, students t- test.
Figure 4
Figure 4
(a) Activation of gp130 in HSF. NFs and HSFs were treated with IL-6•sIL-6Rα for 30 min. Total RNA was subjected to Q-RT-PCR for human gp130 mRNA expression, carried out in triplicate. Shown is fold change mRNA expression relative to GAPDH as internal control. Data represents mean±SD *, p<0.01, students t test. (b) Cell surface activation of gp130 in HSF. Cultured NF and HSF cells were left untreated or IL-6•sIL-6Rα (8ng/ml •25ng/ml) stimulated for 30 min. The expression of cell surface gp130 was analyzed by flow cytometry after staining with anti-gp130-PE. Events were plotted as a function of fluorescence intensity (x-axis). Shaded histograms represent isotype antibody control and open histograms represents either unstimulated anti-gp130-PE stained cells (dotted line) or IL-6•sIL-6Rα stimulated anti-gp130-PE (solid line) as indicated.
Figure 4
Figure 4
(a) Activation of gp130 in HSF. NFs and HSFs were treated with IL-6•sIL-6Rα for 30 min. Total RNA was subjected to Q-RT-PCR for human gp130 mRNA expression, carried out in triplicate. Shown is fold change mRNA expression relative to GAPDH as internal control. Data represents mean±SD *, p<0.01, students t test. (b) Cell surface activation of gp130 in HSF. Cultured NF and HSF cells were left untreated or IL-6•sIL-6Rα (8ng/ml •25ng/ml) stimulated for 30 min. The expression of cell surface gp130 was analyzed by flow cytometry after staining with anti-gp130-PE. Events were plotted as a function of fluorescence intensity (x-axis). Shaded histograms represent isotype antibody control and open histograms represents either unstimulated anti-gp130-PE stained cells (dotted line) or IL-6•sIL-6Rα stimulated anti-gp130-PE (solid line) as indicated.
Figure 5
Figure 5
(a) ECM expression in HSF. NFs and HSFs were stimulated with IL-6•sIL-6Rα and total cellular RNA was subjected to Q-RT-PCR for Col1A2 and FN expression. Shown is fold change mRNA expression relative to GAPDH. *, p<0.01. (b) STAT3 peptide inhibitor attenuates hSOCS3 expression. NF and HSFs were treated with 500 nM STAT3 inhibitor peptide for 6 hoursrs or left untreated. Total cellular RNA (stimulated) was subjected to Q-RT-PCR for hSOCS3 transcript. *, p<0.01. (c) STAT3 peptide inhibitor abrogates FN production in HSF. Cells were treated as in (b) and FN gene expression was measured relative to GAPDH.*, p<0.05. (d) STAT3 peptide inhibitor abrogates Col1A2 production in HSF. Cells were treated as in (b) and Col1A2 gene expression was measured relative to GAPDH. *, p<0.05.
Figure 5
Figure 5
(a) ECM expression in HSF. NFs and HSFs were stimulated with IL-6•sIL-6Rα and total cellular RNA was subjected to Q-RT-PCR for Col1A2 and FN expression. Shown is fold change mRNA expression relative to GAPDH. *, p<0.01. (b) STAT3 peptide inhibitor attenuates hSOCS3 expression. NF and HSFs were treated with 500 nM STAT3 inhibitor peptide for 6 hoursrs or left untreated. Total cellular RNA (stimulated) was subjected to Q-RT-PCR for hSOCS3 transcript. *, p<0.01. (c) STAT3 peptide inhibitor abrogates FN production in HSF. Cells were treated as in (b) and FN gene expression was measured relative to GAPDH.*, p<0.05. (d) STAT3 peptide inhibitor abrogates Col1A2 production in HSF. Cells were treated as in (b) and Col1A2 gene expression was measured relative to GAPDH. *, p<0.05.
Figure 5
Figure 5
(a) ECM expression in HSF. NFs and HSFs were stimulated with IL-6•sIL-6Rα and total cellular RNA was subjected to Q-RT-PCR for Col1A2 and FN expression. Shown is fold change mRNA expression relative to GAPDH. *, p<0.01. (b) STAT3 peptide inhibitor attenuates hSOCS3 expression. NF and HSFs were treated with 500 nM STAT3 inhibitor peptide for 6 hoursrs or left untreated. Total cellular RNA (stimulated) was subjected to Q-RT-PCR for hSOCS3 transcript. *, p<0.01. (c) STAT3 peptide inhibitor abrogates FN production in HSF. Cells were treated as in (b) and FN gene expression was measured relative to GAPDH.*, p<0.05. (d) STAT3 peptide inhibitor abrogates Col1A2 production in HSF. Cells were treated as in (b) and Col1A2 gene expression was measured relative to GAPDH. *, p<0.05.
Figure 5
Figure 5
(a) ECM expression in HSF. NFs and HSFs were stimulated with IL-6•sIL-6Rα and total cellular RNA was subjected to Q-RT-PCR for Col1A2 and FN expression. Shown is fold change mRNA expression relative to GAPDH. *, p<0.01. (b) STAT3 peptide inhibitor attenuates hSOCS3 expression. NF and HSFs were treated with 500 nM STAT3 inhibitor peptide for 6 hoursrs or left untreated. Total cellular RNA (stimulated) was subjected to Q-RT-PCR for hSOCS3 transcript. *, p<0.01. (c) STAT3 peptide inhibitor abrogates FN production in HSF. Cells were treated as in (b) and FN gene expression was measured relative to GAPDH.*, p<0.05. (d) STAT3 peptide inhibitor abrogates Col1A2 production in HSF. Cells were treated as in (b) and Col1A2 gene expression was measured relative to GAPDH. *, p<0.05.
Figure 6
Figure 6
(a) IL-6 trans-signaling increases expression of cellular proliferation markers in HSF. NF and HSF cells were stimulated with IL-6•sIL-6Rα and total cellular RNA was subjected to QPCR for Cyclin D1, c-Myc and Bcl-XL gene expression. Shown is fold change mRNA expression relative to GAPDH as internal control performed in triplicate. Data represents mean ± SD.*, p<0.05, students t test. (b) STAT3 siRNA inhibits expression of cellular proliferation markers in HSF. NF and HSF cells were transfected with either STAT3 siRNA or control siRNA. 72 h after transfection cells were stimulated with IL-6•sIL-6Rα for 30 min and total cellular RNA was subjected to Q-PCR for c-Myc, Bcl-XL and Cyclin D1 gene expression. *, p<0.01, students t test.
Figure 6
Figure 6
(a) IL-6 trans-signaling increases expression of cellular proliferation markers in HSF. NF and HSF cells were stimulated with IL-6•sIL-6Rα and total cellular RNA was subjected to QPCR for Cyclin D1, c-Myc and Bcl-XL gene expression. Shown is fold change mRNA expression relative to GAPDH as internal control performed in triplicate. Data represents mean ± SD.*, p<0.05, students t test. (b) STAT3 siRNA inhibits expression of cellular proliferation markers in HSF. NF and HSF cells were transfected with either STAT3 siRNA or control siRNA. 72 h after transfection cells were stimulated with IL-6•sIL-6Rα for 30 min and total cellular RNA was subjected to Q-PCR for c-Myc, Bcl-XL and Cyclin D1 gene expression. *, p<0.01, students t test.

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