Abstract | INTRODUCTION: T helper (Th)-17 cells are increased in systemic sclerosis (SSc). We therefore assessed whether Th17 cells could modulate the inflammatory and fibrotic responses in dermal fibroblasts from healthy donors (HD) and SSc individuals. METHODS: RESULTS:
IL-17A increased MCP-1, IL-8 and MMP-1 production in a dose-dependent manner while having no effect on type I collagen in HD and SSc fibroblasts both at protein and mRNA levels. Nuclear factor-kappa B (NF-κB) and p38 were preferentially involved in the induction of MCP-1 and IL-8, while MMP-1 was most dependent on c-Jun N-terminal kinase (JNK). Supernatants of activated Th17 clones largely enhanced MCP-1, IL-8 and MMP-1 while strongly inhibiting collagen production. Of note, the production of MCP-1 and IL-8 was higher, while collagen inhibition was lower in SSc compared to HD fibroblasts. The Th17 clone supernatant effects were mostly dependent on additive/synergistic activities between IL-17A, TNF and in part IFN-γ. Importantly, the inhibition of type I collagen production induced by the Th17 clone supernatants was completely abrogated by blockade of IL-17A, TNF and IFN-γ mostly in SSc fibroblasts, revealing an intrinsic resistance to inhibitory signals in SSc. CONCLUSIONS: Our findings demonstrate that in vitro Th17 cells elicit pro-inflammatory responses while restraining collagen production. Thus, the increased Th17 cell number observed in SSc may impact on the inflammatory component of the disease simultaneously potentially providing a protective role against fibrosis.
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Authors | Nicolò Constantino Brembilla, Elisa Montanari, Marie-Elise Truchetet, Elena Raschi, Pierluigi Meroni, Carlo Chizzolini |
Journal | Arthritis research & therapy
(Arthritis Res Ther)
Vol. 15
Issue 5
Pg. R151
(Oct 10 2013)
ISSN: 1478-6362 [Electronic] England |
PMID | 24289089
(Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
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Chemical References |
- CCL2 protein, human
- Chemokine CCL2
- Collagen Type I
- Culture Media, Conditioned
- Inflammation Mediators
- Interleukin-17
- Interleukin-8
- Tumor Necrosis Factor-alpha
- Interferon-gamma
- Matrix Metalloproteinase 1
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Topics |
- Blotting, Western
- Cells, Cultured
- Chemokine CCL2
(genetics, metabolism)
- Collagen Type I
(genetics, metabolism)
- Culture Media, Conditioned
(metabolism, pharmacology)
- Dose-Response Relationship, Drug
- Enzyme-Linked Immunosorbent Assay
- Female
- Fibroblasts
(drug effects, metabolism)
- Gene Expression
(drug effects)
- Humans
- Inflammation Mediators
(metabolism)
- Interferon-gamma
(pharmacology)
- Interleukin-17
(pharmacology)
- Interleukin-8
(genetics, metabolism)
- Male
- Matrix Metalloproteinase 1
(genetics, metabolism)
- Radioimmunoassay
- Reverse Transcriptase Polymerase Chain Reaction
- Scleroderma, Systemic
(genetics, metabolism, pathology)
- Skin
(metabolism, pathology)
- Th17 Cells
(metabolism)
- Tumor Necrosis Factor-alpha
(pharmacology)
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