CXCL10 (alpha) and CCL2 (beta) chemokines in systemic sclerosis--a longitudinal study.

OBJECTIVES To measure serum levels of CXCL10 and CCL2 chemokines in patients with SSc, and relate the findings to clinical phenotype and disease progression. METHODS Serum CXCL10 and CCL2 were assayed in 72 consecutive newly diagnosed SSc patients and in 72 sex- and age-matched controls. In 37 SSc and 37 controls, serum CXCL10 and CCL2 were re-evaluated 5 yrs later. RESULTS SSc at onset showed significantly higher CXCL10 serum levels than controls (216 +/- 126 vs 92 +/- 53 pg/ml; P < 0.0001), as well as CCL2 (388 +/- 172 vs 318 +/- 120 pg/ml; P = 0.01). CXCL10 was significantly increased in SSc with interstitial lung involvement or with kidney involvement (P = 0.01 and P = 0.02, respectively). A significant decrease of CXCL10 was observed from the baseline after 5 yrs in SSc (137 +/- 112 vs 270 +/- 122 pg/ml, respectively; P < 0.0001), while no significant change was observed for CCL2 (418 +/- 176 vs 405 +/- 164 pg/ml; P = NS); the CCL2/CXCL10 ratio significantly increased at the fifth year (1.7 +/- 0.8 vs 3.5 +/- 2.5; P < 0.0001). No significant variations were observed in controls from the basal to the 5-yr evaluation with regards to CXCL10, CCL2 or CCL2/CXCL10 ratio. CONCLUSIONS Our study demonstrates high serum levels of CXCL10 (Th1) and CCL2 (Th2) chemokines in newly diagnosed SSc. High values of CXCL10 are associated with a more severe clinical phenotype (lung and kidney involvement). CXCL10 declined during the follow-up, while CCL2 remained unmodified, suggesting that the disease progresses from the early Th1 inflammatory condition to the advanced Th2-like stage.

[1]  A. Luster,et al.  Chemokines--chemotactic cytokines that mediate inflammation. , 1998, The New England journal of medicine.

[2]  M. Matucci-Cerinic,et al.  Circulating γ/δ T lymphocytes from systemic sclerosis (SSc) patients display a T helper (Th) 1 polarization , 2001 .

[3]  U. Müller-Ladner,et al.  Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cells. , 2006, Arthritis and rheumatism.

[4]  R. Bergamaschi,et al.  Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies , 2001, Journal of Neuroimmunology.

[5]  K. Esposito,et al.  Peripheral Blood T Lymphocytes from Systemic Sclerosis Patients Show Both Th1 and Th2 Activation , 2001, Journal of Clinical Immunology.

[6]  S. Romagnani,et al.  The Th1/Th2 paradigm. , 1997, Immunology today.

[7]  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 .

[8]  M. Rotondi,et al.  Increased serum CXCL10 in Graves' disease or autoimmune thyroiditis is not associated with hyper- or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process. , 2006, European journal of endocrinology.

[9]  R. Strieter,et al.  The role of CXC chemokines in the regulation of angiogenesis in non‐small cell lung cancer , 1997, Journal of leukocyte biology.

[10]  J. Hollander ARTHRITIS AND ALLIED CONDITIONS , 1949 .

[11]  T. Matsushita,et al.  Longitudinal analysis of serum cytokine concentrations in systemic sclerosis: association of interleukin 12 elevation with spontaneous regression of skin sclerosis. , 2006, The Journal of rheumatology.

[12]  W. Karpus,et al.  Differential CC chemokine-induced enhancement of T helper cell cytokine production. , 1997, Journal of immunology.

[13]  P. Libby,et al.  Peroxisome Proliferator-Activated Receptor-γ Activators Inhibit IFN-γ-Induced Expression of the T Cell-Active CXC Chemokines IP-10, Mig, and I-TAC in Human Endothelial Cells1 , 2000, The Journal of Immunology.

[14]  N. Kamatani,et al.  IP-10/MCP-1 ratio in CSF is an useful diagnostic marker of neuropsychiatric lupus patients. , 2006, Rheumatology.

[15]  A. Weetman,et al.  Antithyroid drugs and release of inflammatory mediators by complement-attacked thyroid cells , 1992, The Lancet.

[16]  F. Arnett Is scleroderma an autoantibody mediated disease? , 2006, Current opinion in rheumatology.

[17]  M. Sospedra,et al.  A one-tube polymerase chain reaction protocol demonstrates CC chemokine overexpression in Graves' disease glands. , 1999, The Journal of clinical endocrinology and metabolism.

[18]  P. Lakatos,et al.  Serum interleukin-6 and bone metabolism in patients with thyroid function disorders. , 1997, The Journal of clinical endocrinology and metabolism.

[19]  M. Sebastiani,et al.  Systemic sclerosis following human cytomegalovirus infection , 2002, Annals of the rheumatic diseases.

[20]  S. Bombardieri,et al.  Systemic Sclerosis: Demographic, Clinical, and Serologic Features and Survival in 1,012 Italian Patients , 2002, Medicine.

[21]  S. S. Franceschini,et al.  Interferon-γ-Inducible α-Chemokine CXCL10 Involvement in Graves’ Ophthalmopathy: Modulation by Peroxisome Proliferator-Activated Receptor-γ Agonists , 2006 .

[22]  A. Zlotnik,et al.  Chemokines: a new classification system and their role in immunity. , 2000, Immunity.

[23]  R. Strieter,et al.  The role of CXC chemokines in pulmonary fibrosis. , 2007, The Journal of clinical investigation.

[24]  B. Rollins,et al.  Abnormalities in Monocyte Recruitment and Cytokine Expression in Monocyte Chemoattractant Protein 1–deficient Mice , 1998, The Journal of experimental medicine.

[25]  A. Weetman,et al.  Detection and localization of chemokine gene expression in autoimmune thyroid disease , 2003, Clinical endocrinology.

[26]  M. Salvadori,et al.  High Pretransplant Serum Levels of CXCL10/IP‐10 Are Related to Increased Risk of Renal Allograft Failure , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[27]  D. Askew,et al.  Cutaneous gene expression by DNA microarray in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. , 2007, The Journal of investigative dermatology.

[28]  M. Rotondi,et al.  High levels of circulating CXC chemokine ligand 10 are associated with chronic autoimmune thyroiditis and hypothyroidism. , 2004, The Journal of clinical endocrinology and metabolism.

[29]  T. Yamamoto,et al.  Role of stem cell factor and monocyte chemoattractant protein-1 in the interaction between fibroblasts and mast cells in fibrosis. , 2001, Journal of dermatological science.

[30]  L. Battolla,et al.  Thymus alterations and systemic sclerosis. , 2006, Rheumatology.

[31]  David Abraham,et al.  Systemic sclerosis: a prototypic multisystem fibrotic disorder. , 2007, The Journal of clinical investigation.

[32]  M. Rotondi,et al.  Increase of interferon‐γ‐inducible CXC chemokine CXCL10 serum levels in patients with active Graves’ disease, and modulation by methimazole therapy , 2006, Clinical endocrinology.

[33]  T. Schall,et al.  CC chemokines induce the generation of killer cells from CD56+ cells , 1996, European journal of immunology.

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

[35]  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.

[36]  Jakob S. Jensen,et al.  Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. , 1999, The Journal of clinical investigation.

[37]  M. Rotondi,et al.  Increase of interferon-gamma inducible alpha chemokine CXCL10 but not beta chemokine CCL2 serum levels in chronic autoimmune thyroiditis. , 2005, European journal of endocrinology.

[38]  C. Hellerbrand,et al.  The -2518 promotor polymorphism in the MCP-1 gene is associated with systemic sclerosis. , 2005, The Journal of investigative dermatology.

[39]  Patricia Woo,et al.  Oxford textbook of rheumatology , 1995 .

[40]  R. Corrocher,et al.  Endothelin‐1 serum levels correlate with MCP‐1 but not with homocysteine plasma concentration in patients with systemic sclerosis , 2006, Scandinavian journal of rheumatology.

[41]  C. V. Jensen,et al.  Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis , 2001, European journal of neurology.

[42]  A. McGregor,et al.  EVIDENCE FOR AN EFFECT OF ANTITHYROID DRUGS ON THE NATURAL HISTORY OF GRAVES' DISEASE , 1984, Clinical endocrinology.

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

[44]  M. Rotondi,et al.  Serum levels of the interferon‐γ‐inducible α chemokine CXCL10 in patients with active Graves' disease, and modulation by methimazole therapy and thyroidectomy , 2006 .

[45]  D. Taub,et al.  Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis. , 1995, Journal of immunology.

[46]  Shinichi Sato,et al.  Serum levels of a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, are elevated in patients with systemic sclerosis. , 2004, Journal of dermatological science.

[47]  E. Ferrannini,et al.  Clinical and subclinical autoimmune thyroid disorders in systemic sclerosis. , 2007, European journal of endocrinology.

[48]  G. Mariani,et al.  Iodine-131 Given for Therapeutic Purposes Modulates Differently Interferon-γ-Inducible α-Chemokine CXCL10 Serum Levels in Patients with Active Graves’ Disease or Toxic Nodular Goiter , 2007 .