Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis

Systemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monoki...

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Published in:	Arthritis research & therapy Vol. 13; no. 1; p. R18
Main Authors:	Rabquer, Bradley J, Tsou, Pei-Suen, Hou, Yong, Thirunavukkarasu, Eshwar, Haines, 3rd, G Kenneth, Impens, Ann J, Phillips, Kristine, Kahaleh, Bashar, Seibold, James R, Koch, Alisa E
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 08-02-2011 BioMed Central
Subjects:	Biological response modifiers Chemokine CXCL10 - biosynthesis Chemokine CXCL16 Chemokine CXCL9 - biosynthesis Chemokines Chemokines, CXC - biosynthesis Development and progression Endothelial Cells - metabolism Endothelium Enzyme-Linked Immunosorbent Assay Enzymes Female Fluorescent Antibody Technique Humans Immunohistochemistry Interferon Male Middle Aged Physiological aspects Polymerase Chain Reaction Pulmonary hypertension Receptors, Chemokine - biosynthesis Receptors, Scavenger - biosynthesis Scleroderma (Disease) Scleroderma, Systemic - immunology Scleroderma, Systemic - metabolism Skin Skin - blood supply Skin - metabolism Systemic scleroderma United States
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Summary:	Systemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monokine induced by interferon-γ (IFN-γ) (MIG/CXCL9) and IFN-inducible protein 10 (IP-10/CXCL10), inhibit angiogenesis by binding CXCR3. In addition, CXCL16 promotes angiogenesis by binding its unique receptor CXCR6. In this study, we determined the expression of these chemokines and receptors in SSc skin and serum. Immunohistology and enzyme-linked immunosorbent assays (ELISAs) were used to determine chemokine and chemokine receptor expression in the skin and serum, respectively, of SSc and normal patients. Endothelial cells (ECs) were isolated from SSc skin biopsies and chemokine and chemokine receptor expression was determined by quantitative PCR and immunofluorescence staining. Antiangiogenic IP-10/CXCL10 and MIG/CXCL9 were elevated in SSc serum and highly expressed in SSc skin. However, CXCR3, the receptor for these chemokines, was decreased on ECs in SSc vs. normal skin. CXCL16 was elevated in SSc serum and increased in SSc patients with early disease, pulmonary arterial hypertension, and those that died during the 36 months of the study. In addition, its receptor CXCR6 was overexpressed on ECs in SSc skin. At the mRNA and protein levels, CXCR3 was decreased while CXCR6 was increased on SSc ECs vs. human microvascular endothelial cells (HMVECs). These results show that while the expression of MIG/CXCL9 and IP-10/CXCL10 are elevated in SSc serum, the expression of CXCR3 is downregulated on SSc dermal ECs. In contrast, CXCL16 and CXCR6 are elevated in SSc serum and on SSc dermal ECs, respectively. In all, these findings suggest angiogenic chemokine receptor expression is likely regulated in an effort to promote angiogenesis in SSc skin.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1478-6362 1478-6354 1478-6362
DOI:	10.1186/ar3242