Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor β.

Abstract

OBJECTIVE:

To explore the expression of thymic stromal lymphopoietin (TSLP) in patients with diffuse cutaneous systemic sclerosis (dcSSc) and compare its effects in vivo and in vitro with those of interleukin-13 (IL-13) and transforming growth factor β (TGFβ).

METHODS:

Skin biopsy specimens from patients with dcSSc (n = 14) and healthy controls (n = 13) were analyzed by immunohistochemistry and immunofluorescence for TSLP, TSLP receptor, CD4, CD8, CD31, and CD163 markers. Wild-type, IL-4Rα1-, and TSLP-deficient mice were treated with TGFβ, IL-13, poly(I-C), or TSLP by osmotic pump. Human fibroblasts and peripheral blood mononuclear cells (PBMCs) were stimulated with TGFβ, IL-13, poly(I-C), or TSLP. Microarray analysis and quantitative polymerase chain reaction were performed to determine gene expression, and protein levels of phospho-Smad2 and macrophage marker CD163 were tested.

RESULTS:

TSLP was highly expressed in the skin of dcSSc patients, more strongly in perivascular areas and in immune cells, and was produced mainly by CD163+ cells. The skin of TSLP-treated mice showed up-regulated clusters of gene expression that overlapped strongly with those in IL-13- and TGFβ-treated mice. TSLP up-regulated specific genes, including CXCL9, proteasome, and interferon (IFN)-regulated genes. TSLP treatment in IL-4Rα1-deficient mice promoted similar cutaneous inflammation as in wild-type mice, though TSLP-induced arginase 1, CCL2, and matrix metalloproteinase 12 messenger RNA levels were blocked. In PBMCs, TSLP up-regulated tumor necrosis factor α, Mx-1, IFNγ, CXCL9, and mannose receptor 1 gene expression. TSLP-deficient mice treated with TGFβ showed less fibrosis and blocked expression of plasminogen activator inhibitor 1 and osteopontin 1. Poly(I-C)-treated mice showed high levels of cutaneous TSLP.

CONCLUSION:

TSLP is highly expressed in the skin of dcSSc patients and interacts in a complex manner with 2 other profibrotic cytokines, TGFβ and IL-13, strongly suggesting that it might promote SSc fibrosis directly or indirectly by synergistically stimulating profibrotic genes, or production of these cytokines.

• Authors: Romy B Christmann, Allison Mathes, Alsya J Affandi, Cristina Padilla, Banafsheh Nazari, Andreea M Bujor, Giuseppina Stifano, Robert Lafyatis
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 65 Issue 5 Pg. 1335-46 (May 2013) ISSN: 1529-0131 [Electronic] United States
• PMID: 23335246 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 by the American College of Rheumatology.

Chemical References

• Biomarkers
• Cytokines
• Interleukin-13
• Intracellular Signaling Peptides and Proteins
• RNA, Messenger
• Transforming Growth Factor beta
• Poly I-C
• Thymic Stromal Lymphopoietin

Topics

• Animals
• Biomarkers (metabolism)
• Cytokines (biosynthesis, deficiency, pharmacology)
• Fibroblasts (drug effects, metabolism, pathology)
• Fibrosis (genetics)
• Gene Expression (drug effects)
• Humans
• Interleukin-13 (metabolism, pharmacology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• Poly I-C (pharmacology)
• RNA, Messenger (metabolism)
• Scleroderma, Diffuse (diagnosis, metabolism)
• Skin (metabolism, pathology)
• Transforming Growth Factor beta (metabolism, pharmacology)
• Up-Regulation
• Thymic Stromal Lymphopoietin