Down-regulation of fibrinogen biosynthesis by IL-4, IL-10 and IL-13.
High levels of fibrinogen are recognized as an important vascular risk factor; however, it is not known if the increase of plasma fibrinogen is directly responsible for this risk, or is only a marker of vascular inflammation. To support this second hypothesis, Oncostatin M (OSM) is a potent stimulator of fibrinogen biosynthesis and induces smooth muscle cell proliferation. In the same way, we analysed whether interleukin-4 (IL-4), interleukin-10 (IL-10) or interleukin-13 (IL-13), which protect vessel walls from monocytes injuries leading to atherosclerosis, could influence fibrinogen biosynthesis. The two levels of regulation of fibrinogen biosynthesis were tested: firstly, the direct effect of these cytokines on fibrinogen production by the hepatoma cell line Hep G2, and secondly their effect on the secretion of hepatocyte stimulating factor (HSF) activity in the supernatant of lipopolysaccharide (LPS)-activated monocytes. IL-4 and IL-13 added to Hep G2 cells down-regulated both the increase of fibrinogen secretion induced by IL-6 and fibrinogen mRNA levels, this effect being more pronounced when Hep G2 were preincubated with the two cytokines before IL-6 addition. The effect of IL-10 was evidenced only on mRNA expression. IL-10 and IL-13 dose-dependently decrease HSF activity secreted by LPS-activated monocytes, whereas IL-4 had no effect. However, the three cytokines decreased HSF activity when monocytes were incubated with the cytokines before LPS activation. The effects of these cytokines on HSF activity are related to variations of IL-6 and OSM secretion. Our data strengthen the hypothesis that the fibrinogen level is a marker of vascular disease, since cytokines which have a protective vascular effect down-regulate fibrinogen production.
Vasse
M
M
Faculté de Médecine et de Pharmacie de Rouen, Saint-Etienne du Rouvray, France.
Paysant
I
I
Soria
J
J
Mirshahi
S S
SS
Vannier
J P
JP
Soria
C
C
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology; D002460:Cell Line; D015536:Down-Regulation; D005340:Fibrinogen / Q000096:biosynthesis*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000378:metabolism; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism
D018793:Interleukin-13; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D053683:Oncostatin M; D016753:Interleukin-10; D015847:Interleukin-4; D005340:Fibrinogen