Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cells.
OBJECTIVE
Monocyte chemoattractant protein 1 (MCP-1; CCL2) has been implicated in the pathogenesis of fibrotic diseases and is up-regulated in patients with systemic sclerosis (SSc). The aim of the present study was to examine the mechanisms by which MCP-1 mediates its profibrotic effects in the setting of SSc.


METHODS
The expression of receptors for MCP-1 on dermal fibroblasts was analyzed by real-time polymerase chain reaction and fluorescence-activated cell sorting. The ability of extracellular matrix proteins to bind and release MCP-1 was quantified by enzyme-linked immunosorbent assay. Th0 cells were isolated using a magnetic-activated cell sorting system and were stimulated twice in the presence of MCP-1. The synthesis of collagen was measured using the Sircol collagen assay kit.


RESULTS
The glycosaminoglycan chondroitin sulfate, but not fibronectin or collagens, bound and released MCP-1 in a time-dependent manner. MCP-1 that was released from chondroitin sulfate induced the differentiation of interleukin-4 (IL-4)-producing T cells in a dose-dependent manner. In turn, dermal fibroblasts from patients with SSc expressed IL-4 receptor, and stimulation with IL-4 significantly increased the production of collagen in dermal fibroblasts. In contrast, CCR2a and CCR2b, as well as D6 and US28 (other potential receptors of MCP-1), were not detectable in SSc and normal fibroblasts, and their expression was not induced by platelet-derived growth factor, IL-1beta, or IL-4. In addition, MCP-1 had no direct effects on collagen production by fibroblasts.


CONCLUSIONS
MCP-1 has no direct effects on dermal fibroblasts but contributes to fibrosis in patients with SSc by inducing the differentiation of IL-4-producing T cells. Because MCP-1 has both proinflammatory and profibrotic effects, pharmacologic targeting of MCP-1 could be a promising therapeutic approach in SSc.
Distler
Jörg H W
JH
Center of Experimental Rheumatology, Dept. of Rheumatology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Jüngel
Astrid
A
Caretto
David
D
Schulze-Horsel
Ursula
U
Kowal-Bielecka
Otylia
O
Gay
Renate E
RE
Michel
Beat A
BA
Müller-Ladner
Ulf
U
Kalden
Joachim R
JR
Gay
Steffen
S
Distler
Oliver
O
D000293:Adolescent; D000328:Adult; D000368:Aged; D018932:Chemokine CCL2 / Q000502:physiology*; D005260:Female; D005355:Fibrosis / Q000209:etiology; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism*
D018932:Chemokine CCL2; D006025:Glycosaminoglycans; D015847:Interleukin-4