Treatment with sulfasalazine or sulfapyridine, but not 5-aminosalicylic acid, inhibits basic fibroblast growth factor-induced endothelial cell chemotaxis
Mv. Volin et al., Treatment with sulfasalazine or sulfapyridine, but not 5-aminosalicylic acid, inhibits basic fibroblast growth factor-induced endothelial cell chemotaxis, ARTH RHEUM, 42(9), 1999, pp. 1927-1935
Objective, Rheumatoid arthritis (RA) is characterized by leukocyte recruitm
ent and angiogenesis. We investigated the effects of sulfasalazine (SSZ) an
d its metabolites, sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA), on
components of angiogenesis, namely, endothelial cell (EC) chemotaxis and p
roliferation, as well as on EC chemokine and soluble adhesion molecule expr
ession.
Methods. SSZ, SP, and 5-ASA were assayed for their effects on basic fibrobl
ast 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
a (GRO alpha), epithelial neutrophil-activating peptide 78 (ENA-78), solubl
e 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 chem
otaxis (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 < 0.0
5 [n = 5]), SSZ inhibited phorbol 12-myristate 13-acetate-induced HMVEC tub
e formation (P < 0.05; [minimum n = 5]), Tumor necrosis factor alpha-stimul
ated HMVEC shedding of sICAM-1 was reduced by incubation with either SSZ (1
9%) or 5-ASA (23%) (P < 0.05; [n = 6]), SP inhibited cytokine-stimulated HM
VEC expression of IL-8 and MCP-1 (P < 0.05; [n = 4]), Neither SSZ nor its m
etabolites had any effect on HMVEC production of sE-selectin, GRO alpha, or
ENA-78,
Conclusion. These results demonstrate that SSZ and its metabolite SP may af
fect the pathogenesis of RA by inhibiting EC chemotaxis, proliferation, tub
e formation, and expression of sICAM-1, IL-8, and MCP-1.