title: Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Dr., Ann Arbor, MI 48109, USA. brabquer@med.umich.edu
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Rabquer
authors.forename: Pei-Suen
authors.initials: PS
authors.lastname: Tsou
authors.forename: Yong
authors.initials: Y
authors.lastname: Hou
authors.forename: Eshwar
authors.initials: E
authors.lastname: Thirunavukkarasu
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Impens
authors.forename: Kristine
authors.initials: K
authors.lastname: Phillips
authors.forename: Bashar
authors.initials: B
authors.lastname: Kahaleh
authors.forename: James R
authors.initials: JR
authors.lastname: Seibold
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
mesh_terms: D054357:Chemokine CXCL10 / Q000096:biosynthesis*; D000075743:Chemokine CXCL16; D054370:Chemokine CXCL9 / Q000096:biosynthesis*; D019743:Chemokines, CXC / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D051116:Receptors, Scavenger / Q000096:biosynthesis*; D012595:Scleroderma, Systemic / Q000276:immunology / Q000378:metabolism*; D012867:Skin / Q000098:blood supply / Q000378:metabolism
chemical_list: C423727:CXCL16 protein, human; D054357:Chemokine CXCL10; D000075743:Chemokine CXCL16; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger