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The expression profile of the toll-like receptor family in scleroderma dermal fibroblasts
A Sakoguchi1, W Nakayama, M Jinnin
1Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. pediatric-dr.a@canvas.ocn.ne.jp.
Objectives:
The toll-like receptor (TLR) family is thought to be expressed in many cell types in the skin and play a role in various diseases. The expression pattern and role of TLRs in systemic sclerosis (SSc) is to be clarified. We investigated the expression profiles of TLR-related genes in SSc fibroblasts, and tried to clarify their roles in the pathogenesis of this disease.
Methods:
The expression profile of TLR-related genes was assessed by gene array. Real-time PCR was used to confirm the array result. The protein expression of TLRs and type I collagen was determined by immunoblotting and immunohistochemistry.
Results:
PCR array revealed that several genes were up- or down-regulated in SSc fibroblasts compared to normal cells. Among them, both mRNA and protein levels of TLR5 and TLR10 were up-regulated in SSc fibroblasts. The transfection of Smad3 siRNA into SSc fibroblasts resulted in the down-regulation of TLR proteins. There was no significant difference in mRNA half-lives of TLR5 and TLR10 between normal and SSc fibroblasts. Immunohistochemical staining revealed that TLRs expression was strongly detected in SSc fibroblasts in vivo. The stimulation of TLR5 signal with flagellin reduced the expression of type I collagen in SSc fibroblasts, but not in normal fibroblasts.
Conclusions:
TLR5 and TLR10 expression is increased in SSc fibroblasts in vitro and in vivo, probably at transcript level via the TGF-β/Smad3 activation. Furthermore, TLR5 itself may have suppressive effects on collagen expression, and its overexpression in SSc fibroblasts may be the negative feedback against tissue fibrosis.
Insights
Toll-like receptors (TLRs) like TLR5 and TLR10 are upregulated in systemic sclerosis (SSc) fibroblasts. TLR5 activation may suppress collagen production, potentially acting as a negative feedback mechanism against fibrosis in SSc.
Area of Science:
- Dermatology
- Immunology
- Molecular Biology
Background:
- Toll-like receptors (TLRs) are implicated in various skin diseases.
- The role and expression of TLRs in systemic sclerosis (SSc) remain unclear.
Purpose of the Study:
- To investigate TLR gene expression profiles in SSc fibroblasts.
- To elucidate the role of TLRs in the pathogenesis of SSc.
Main Methods:
- Gene array analysis to assess TLR-related gene expression.
- Real-time PCR, immunoblotting, and immunohistochemistry to validate mRNA and protein levels.
- Investigated the effect of TLR5 stimulation on collagen expression.
Main Results:
- TLR5 and TLR10 mRNA and protein levels were significantly upregulated in SSc fibroblasts.
- TLR expression was confirmed in SSc fibroblasts in vivo.
- TLR5 stimulation reduced type I collagen expression in SSc fibroblasts.
Conclusions:
- Increased TLR5 and TLR10 expression in SSc fibroblasts is likely mediated by TGF-β/Smad3 signaling.
- TLR5 activation may suppress collagen production, potentially counteracting SSc-related fibrosis.
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