Molecular aspects of regulation of collagen gene expression in fibrosis

Rashpal K. Bhogal; Cristina M. Stoica; Tracy L. McGaha; Constantin A. Bona

doi:10.1007/s10875-005-7827-3

Molecular aspects of regulation of collagen gene expression in fibrosis

Rashpal K. Bhogal, Cristina M. Stoica, Tracy L. McGaha, Constantin A. Bona^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

80 Scopus citations

Abstract

Fibrosis, the hyper-accumulation of scar tissue, is characterized by the overproduction and deposition of type I and III collagen by fibroblasts and is the one of the main pathologic outcomes of the autoimmune disorder scleroderma. While the causes of fibrosis in scleroderma are unknown, cytokines such as TGF-β, IL-4 and IL-13, play a crucial role in the stimulation of collagen production have been implicated in the disease process. In fibroblasts stimulation of collagen production by these cytokines is dependent on the Smad and STAT6 signaling pathways induced by TGF-β and IL-4, IL-13 respectively. Furthermore, mounting evidence suggest cytokine crosstalk is relevant in the sclerotic process. Our laboratory demonstrated an increase in TGF-β1 gene transcription from fibroblasts stimulated with IL-4. In addition, TSK/+ mice lacking the IL-4α receptor show impaired transcription of the TGF-β1 gene and did not display fibrosis. Likewise, it appears that STAT6 plays a role in fibroblast TGF-β1 transcription after IL-4 or IL-13 stimulation. These findings suggest that an epistatic interaction between IL-4 and TGF-β may exist which is crucial for pathologic sclerotic activity.

Original language	English (US)
Pages (from-to)	592-603
Number of pages	12
Journal	Journal of Clinical Immunology
Volume	25
Issue number	6
DOIs	https://doi.org/10.1007/s10875-005-7827-3
State	Published - Nov 2005
Externally published	Yes

Funding

This work was supported by a NAIDI grant: R01 AI055737. Murine TGF-β1 promoter/CAT constructs were kindly donated by Dr. Seong-Jin Kim, National Cancer Institute, Bethesda, MD. The plasmid pcDNA3-STAT6 VT, containing a constitutively activated STAT6 (STAT6 VT) was kindly donated by Dr. William Paul (NIH/NIAID, Bethesda, MD). A pcDNA3 plasmid containing complementary DNA (cDNA) for murine STAT6 (STAT6 wt) was a gift from Dr. Curt Hovath, Mount Sinai School of Medicine, New York, NY. The STAT6 ΔCplas-mid was kindly provided by Dr. Ulrike Schindler (Tularik, South San Francisco, CA).

Keywords

Collagen
Fibroblasts
Fibrosis
Pro-fibrogenic cytokines
Scleroderma

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1007/s10875-005-7827-3

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@article{fca3444eadf54b6cbab0d71db24a9594,

title = "Molecular aspects of regulation of collagen gene expression in fibrosis",

abstract = "Fibrosis, the hyper-accumulation of scar tissue, is characterized by the overproduction and deposition of type I and III collagen by fibroblasts and is the one of the main pathologic outcomes of the autoimmune disorder scleroderma. While the causes of fibrosis in scleroderma are unknown, cytokines such as TGF-β, IL-4 and IL-13, play a crucial role in the stimulation of collagen production have been implicated in the disease process. In fibroblasts stimulation of collagen production by these cytokines is dependent on the Smad and STAT6 signaling pathways induced by TGF-β and IL-4, IL-13 respectively. Furthermore, mounting evidence suggest cytokine crosstalk is relevant in the sclerotic process. Our laboratory demonstrated an increase in TGF-β1 gene transcription from fibroblasts stimulated with IL-4. In addition, TSK/+ mice lacking the IL-4α receptor show impaired transcription of the TGF-β1 gene and did not display fibrosis. Likewise, it appears that STAT6 plays a role in fibroblast TGF-β1 transcription after IL-4 or IL-13 stimulation. These findings suggest that an epistatic interaction between IL-4 and TGF-β may exist which is crucial for pathologic sclerotic activity.",

keywords = "Collagen, Fibroblasts, Fibrosis, Pro-fibrogenic cytokines, Scleroderma",

author = "Bhogal, {Rashpal K.} and Stoica, {Cristina M.} and McGaha, {Tracy L.} and Bona, {Constantin A.}",

note = "Funding Information: This work was supported by a NAIDI grant: R01 AI055737. Murine TGF-β1 promoter/CAT constructs were kindly donated by Dr. Seong-Jin Kim, National Cancer Institute, Bethesda, MD. The plasmid pcDNA3-STAT6 VT, containing a constitutively activated STAT6 (STAT6 VT) was kindly donated by Dr. William Paul (NIH/NIAID, Bethesda, MD). A pcDNA3 plasmid containing complementary DNA (cDNA) for murine STAT6 (STAT6 wt) was a gift from Dr. Curt Hovath, Mount Sinai School of Medicine, New York, NY. The STAT6 ΔCplas-mid was kindly provided by Dr. Ulrike Schindler (Tularik, South San Francisco, CA).",

year = "2005",

month = nov,

doi = "10.1007/s10875-005-7827-3",

language = "English (US)",

volume = "25",

pages = "592--603",

journal = "Journal of Clinical Immunology",

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T1 - Molecular aspects of regulation of collagen gene expression in fibrosis

AU - Bhogal, Rashpal K.

AU - Stoica, Cristina M.

AU - McGaha, Tracy L.

AU - Bona, Constantin A.

N1 - Funding Information: This work was supported by a NAIDI grant: R01 AI055737. Murine TGF-β1 promoter/CAT constructs were kindly donated by Dr. Seong-Jin Kim, National Cancer Institute, Bethesda, MD. The plasmid pcDNA3-STAT6 VT, containing a constitutively activated STAT6 (STAT6 VT) was kindly donated by Dr. William Paul (NIH/NIAID, Bethesda, MD). A pcDNA3 plasmid containing complementary DNA (cDNA) for murine STAT6 (STAT6 wt) was a gift from Dr. Curt Hovath, Mount Sinai School of Medicine, New York, NY. The STAT6 ΔCplas-mid was kindly provided by Dr. Ulrike Schindler (Tularik, South San Francisco, CA).

PY - 2005/11

Y1 - 2005/11

N2 - Fibrosis, the hyper-accumulation of scar tissue, is characterized by the overproduction and deposition of type I and III collagen by fibroblasts and is the one of the main pathologic outcomes of the autoimmune disorder scleroderma. While the causes of fibrosis in scleroderma are unknown, cytokines such as TGF-β, IL-4 and IL-13, play a crucial role in the stimulation of collagen production have been implicated in the disease process. In fibroblasts stimulation of collagen production by these cytokines is dependent on the Smad and STAT6 signaling pathways induced by TGF-β and IL-4, IL-13 respectively. Furthermore, mounting evidence suggest cytokine crosstalk is relevant in the sclerotic process. Our laboratory demonstrated an increase in TGF-β1 gene transcription from fibroblasts stimulated with IL-4. In addition, TSK/+ mice lacking the IL-4α receptor show impaired transcription of the TGF-β1 gene and did not display fibrosis. Likewise, it appears that STAT6 plays a role in fibroblast TGF-β1 transcription after IL-4 or IL-13 stimulation. These findings suggest that an epistatic interaction between IL-4 and TGF-β may exist which is crucial for pathologic sclerotic activity.

AB - Fibrosis, the hyper-accumulation of scar tissue, is characterized by the overproduction and deposition of type I and III collagen by fibroblasts and is the one of the main pathologic outcomes of the autoimmune disorder scleroderma. While the causes of fibrosis in scleroderma are unknown, cytokines such as TGF-β, IL-4 and IL-13, play a crucial role in the stimulation of collagen production have been implicated in the disease process. In fibroblasts stimulation of collagen production by these cytokines is dependent on the Smad and STAT6 signaling pathways induced by TGF-β and IL-4, IL-13 respectively. Furthermore, mounting evidence suggest cytokine crosstalk is relevant in the sclerotic process. Our laboratory demonstrated an increase in TGF-β1 gene transcription from fibroblasts stimulated with IL-4. In addition, TSK/+ mice lacking the IL-4α receptor show impaired transcription of the TGF-β1 gene and did not display fibrosis. Likewise, it appears that STAT6 plays a role in fibroblast TGF-β1 transcription after IL-4 or IL-13 stimulation. These findings suggest that an epistatic interaction between IL-4 and TGF-β may exist which is crucial for pathologic sclerotic activity.

KW - Collagen

KW - Fibroblasts

KW - Fibrosis

KW - Pro-fibrogenic cytokines

KW - Scleroderma

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SN - 0271-9142

VL - 25

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EP - 603

JO - Journal of Clinical Immunology

JF - Journal of Clinical Immunology

IS - 6

ER -

Molecular aspects of regulation of collagen gene expression in fibrosis

Abstract

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Keywords

ASJC Scopus subject areas

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