Tumour-necrosis factor-α induces heparan sulfate 6-O-endosulfatase 1 (Sulf-1) expression in fibroblasts.
Heparan sulfate (HS) 6-O-endosulfatases (Sulfs) have emerged recently as critical regulators of many physiological and pathological processes. By removing 6-O-sulfates from specific HS sequences, they modulate the activities of a variety of growth factors and morphogens, including fibroblast growth factor (FGF)-1. However, little is known about the functions of Sulfs in inflammation. Tumour-necrosis factor (TNF)-α plays an important role in regulating the behaviour of fibroblasts. In this study, we examined the effect of this inflammatory cytokine on the expression of Sulfs in human MRC-5 fibroblasts. Compositional analysis of HS from TNF-α-treated cells showed a strong reduction in the amount of the trisulfated UA2S-GlcNS6S disaccharide, which suggested a selective reaction of 6-O-desulfation. Real-time PCR analysis revealed that TNF-α increased Sulf-1 expression in a dose- and time-dependent manner, via a mechanism involving NF-ĸB, ERK1/2 and p38 MAPK. In addition, we confirmed that cell stimulation with TNF-α was accompanied by the secretion of an active form of Sulf-1. To study the function of Sulf- 1, we examined the responses induced by FGF-1. We showed that ERK1/2 activation and cell proliferation were markedly reduced in TNF-α-treated MRC-5 cells compared with untreated cells. Silencing the expression of Sulf-1 by RNA interference restored the responses induced by FGF-1, which indicated that TNF-α-mediated induction of the sulfatase indeed resulted in alterations of HS biological properties. Taken together, our results indicate that Sulf-1 is responsive to TNF-α stimulation and may function as an autocrine regulator of fibroblast expansion in the course of an inflammatory response.
University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
Anne-Sophie
AS
Sikora
University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
Charles
C
Hellec
University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
Mathieu
M
Carpentier
University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
Pierre
P
Martinez
University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
Maxime
M
Delos
University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
Agnès
A
Denys
University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France. Electronic address: fabrice.allain@univ-lille1.fr.
Fabrice
F
Allain
D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D015238:Sulfotransferases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006497:Heparan Sulfate; D015238:Sulfotransferases; D014409:Tumor Necrosis Factor-alpha; C470791:SULF1 protein, human
Fibroblast; Heparan sulfates; Inflammation; Sulf