The -2518 promotor polymorphism in the MCP-1 gene is associated with systemic sclerosis.

Factors influencing the initiation or progression of sclerosis in patients with systemic sclerosis (SSc) are poorly understood. Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine, which is upregulated in fibroblasts during development of sclerosis. In this study, we investigated the frequency of the functional -2518G MCP-1 promoter polymorphism in 18 patients with SSc and 139 healthy controls. In the lesional skin of the same SSc patients, expression of MCP-1 protein was examined by immunohistochemistry. To investigate a genotype/phenotype correlation, basal as well as tumor necrosis factor (TNF)-induced MCP-1 expression was analyzed in fibroblasts isolated from the skin of SSc patients with different MCP-1 genotypes by quantitative RT-PCR and ELISA. Genotyping for the -2518 (A/G) MCP-1 promotor polymorphism showed that GG homozygotes were significantly more frequent in patients with SSc than in controls (28%vs 6%). Results of immunohistochemistry revealed that MCP-1 was expressed in keratinocytes, infiltrating inflammatory cells, fibroblasts, and endothelial cells in scleroderma skin, whereas normal control skin showed no MCP-1 expression. MCP-1 expression in fibroblasts from GG-homozygote individuals tended to be stronger as compared to AG or AA genotypes. Furthermore, basal as well as TNF-induced MCP-1 expression of fibroblasts isolated from a GG-homozygote SSc patient was significantly higher than MCP-1 expression of fibroblasts isolated from heterozygote or AA-homozygote donors. The A -2518G polymorphism of the MCP-1 gene appears to affect MCP-1 expression of skin fibroblasts of patients with SSc. In accordance, the G/G genotype may predispose patients to SSc.

[1]  A. Bosserhoff,et al.  A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease. , 2003, Gastroenterology.

[2]  Toshiyuki Yamamoto,et al.  Role of monocyte chemoattractant protein-1 and its receptor,CCR-2, in the pathogenesis of bleomycin-induced scleroderma. , 2003, The Journal of investigative dermatology.

[3]  C. Hellerbrand,et al.  Polymorphism of monocyte chemoattractant protein 1 in Crohn's disease , 2003, International Journal of Colorectal Disease.

[4]  B. Krämer,et al.  A Monocyte chemoattractant protein-1 (MCP-1) polymorphism and outcome after renal transplantation. , 2002, Journal of the American Society of Nephrology : JASN.

[5]  M. Landthaler,et al.  Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis. , 2001, Arthritis and rheumatism.

[6]  J. Ioannidis,et al.  Replication validity of genetic association studies , 2001, Nature Genetics.

[7]  J. Sánchez-Román,et al.  MCP-1 promoter polymorphism in Spanish patients with systemic lupus erythematosus. , 2001, Tissue antigens.

[8]  T. Yamamoto,et al.  High expression and autoinduction of monocyte chemoattractant protein‐1 in scleroderma fibroblasts , 2001, European journal of immunology.

[9]  A. Falus,et al.  Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity. , 2001, The Journal of allergy and clinical immunology.

[10]  Z. Prohászka,et al.  Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 -2518 G/G genotype in CAD patients. , 2001, Atherosclerosis.

[11]  T. Yamamoto,et al.  Expression of monocyte chemoattractant protein-1 in the lesional skin of systemic sclerosis. , 2001, Journal of dermatological science.

[12]  J. Alcamí,et al.  Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression. , 2001, Arthritis and rheumatism.

[13]  J. English,et al.  Localized and systemic scleroderma. , 2001, Seminars in cutaneous medicine and surgery.

[14]  Toshiyuki Yamamoto,et al.  Monocyte Chemoattractant Protein-1 Enhances Gene Expression and Synthesis of Matrix Metalloproteinase-1 in Human Fibroblasts by an Autocrine IL-1α Loop1 , 2000, The Journal of Immunology.

[15]  T. Sugaya,et al.  Cell to cell interaction between mesangial cells and macrophages induces the expression of monocyte chemoattractant protein-1 through nuclear factor-kappaB activation. , 2000, Biochemical and Biophysical Research Communications - BBRC.

[16]  Sato,et al.  Augmented production of chemokines (monocyte chemotactic protein‐1 (MCP‐1), macrophage inflammatory protein‐1α (MIP‐1α) and MIP‐1β) in patients with systemic sclerosis: MCP‐1 and MIP‐1α may be involved in the development of pulmonary fibrosis , 1999 .

[17]  B. Rovin,et al.  A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. , 1999, Biochemical and biophysical research communications.

[18]  S. Milani,et al.  Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. , 1998, The American journal of pathology.

[19]  D. Salant,et al.  RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis , 1997, The Journal of experimental medicine.

[20]  S. Phan,et al.  Costimulation of Fibroblast Collagen and Transforming Growth Factor β1 Gene Expression by Monocyte Chemoattractant Protein-1 via Specific Receptors* , 1996, The Journal of Biological Chemistry.

[21]  E. Kovacs,et al.  Fibrogenic cytokines and connective tissue production , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  R. Danner,et al.  Neutrophil attractant protein-1 and monocyte chemoattractant protein-1 in human serum. Effects of intravenous lipopolysaccharide on free attractants, specific IgG autoantibodies and immune complexes. , 1993, Journal of immunology.

[23]  A. J. Valente,et al.  Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[24]  A. Masi.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). , 1980, Bulletin on the rheumatic diseases.

[25]  James F. Fries,et al.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. , 1980, Arthritis and rheumatism.

[26]  B. Rollins,et al.  Monocyte chemoattractant protein-1. , 1999, Chemical immunology.

[27]  S. Kunkel,et al.  Novel roles for chemokines and fibroblasts in interstitial fibrosis. , 1998, Kidney international.