title: Treatment with sulfasalazine or sulfapyridine, but not 5-aminosalicyclic acid, inhibits basic fibroblast growth factor-induced endothelial cell chemotaxis.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is characterized by leukocyte recruitment and angiogenesis. We investigated the effects of sulfasalazine (SSZ) and its metabolites, sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA), on components of angiogenesis, namely, endothelial cell (EC) chemotaxis and proliferation, as well as on EC chemokine and soluble adhesion molecule expression.
  
  
  METHODS
  SSZ, SP, and 5-ASA were assayed for their effects on basic fibroblast growth factor (bFGF)-induced human dermal microvascular endothelial cell (HMVEC) chemotaxis and proliferation. EC were plated on Matrigel to assess the effect of SSZ on EC tube formation. Enzyme-linked immunosorbent assays were performed to determine changes in HMVEC production of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), growth-related oncogene alpha (GROalpha), epithelial neutrophil-activating peptide 78 (ENA-78), soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule 1 (sICAM-1) upon treatment with SSZ or its metabolites.
  
  
  RESULTS
  HMVEC incubated with SSZ or SP exhibited reduced bFGF-induced chemotaxis (59%, [n = 7] and 22%, [n = 3], respectively) (P<0.05). SSZ and SP decreased basal HMVEC proliferation, while 5-ASA increased proliferation (P<0.05; [n = 5]). SSZ decreased bFGF-induced HMVEC proliferation (P<0.05 [n = 5]). SSZ inhibited phorbol 12-myristate 13-acetate-induced HMVEC tube formation (P<0.05; [minimum n = 5]). Tumor necrosis factor alpha-stimulated HMVEC shedding of sICAM-1 was reduced by incubation with either SSZ (19%) or 5-ASA (23%) (P<0.05; [n = 6]). SP inhibited cytokine-stimulated HMVEC expression of IL-8 and MCP-1 (P<0.05; [n = 4]). Neither SSZ nor its metabolites had any effect on HMVEC production of sE-selectin, GROalpha, or ENA-78.
  
  
  CONCLUSIONS
  These results demonstrate that SSZ and its metabolite SP may affect the pathogenesis of RA by inhibiting EC chemotaxis, proliferation, tube formation, and expression of sICAM-1, IL-8, and MCP-1.
authors.affiliation: Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Volin
authors.forename: L A
authors.initials: LA
authors.lastname: Harlow
authors.forename: J M
authors.initials: JM
authors.lastname: Woods
authors.forename: P L
authors.initials: PL
authors.lastname: Campbell
authors.forename: M A
authors.initials: MA
authors.lastname: Amin
authors.forename: M
authors.initials: M
authors.lastname: Tokuhira
authors.forename: A E
authors.initials: AE
authors.lastname: Koch
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001672:Biocompatible Materials; D002455:Cell Division / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis; D002633:Chemotaxis / Q000187:drug effects*; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis; D007797:Laminin; D019804:Mesalamine / Q000494:pharmacology / Q000627:therapeutic use*; D011509:Proteoglycans; D012995:Solubility; D013427:Sulfapyridine / Q000494:pharmacology / Q000627:therapeutic use*; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001672:Biocompatible Materials; D018932:Chemokine CCL2; D004338:Drug Combinations; D007375:Interleukin-1; D016209:Interleukin-8; D007797:Laminin; D011509:Proteoglycans; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D018799:Intercellular Adhesion Molecule-1; D012460:Sulfasalazine; D019804:Mesalamine; D003094:Collagen; D013427:Sulfapyridine