Proinflammatory cytokines induce hyaluronan synthesis and monocyte adhesion in human endothelial cells through hyaluronan synthase 2 (HAS2) and the nuclear factor-kappaB (NF-kappaB) pathway.
Chronic inflammation is now accepted to have a critical role in the onset of several diseases as well as in vascular pathology, where macrophage transformation into foam cells contributes in atherosclerotic plaque formation. Endothelial cells (EC) have a critical function in recruitment of immune cells, and proinflammatory cytokines drive the specific expression of several adhesion proteins. During inflammatory responses several cells produce hyaluronan matrices that promote monocyte/macrophage adhesion through interactions with the hyaluronan receptor CD44 present on inflammatory cell surfaces. In this study, we used human umbilical chord vein endothelial cells (HUVECs) as a model to study the mechanism that regulates hyaluronan synthesis after treatment with proinflammatory cytokines. We found that interleukin 1beta and tumor necrosis factors alpha and beta, but not transforming growth factors alpha and beta, strongly induced HA synthesis by NF-kappaB pathway. This signaling pathway mediated hyaluronan synthase 2 (HAS2) mRNA expression without altering other glycosaminoglycan metabolism. Moreover, we verified that U937 monocyte adhesion on stimulated HUVECs depends strongly on hyaluronan, and transfection with short interference RNA of HAS2 abrogates hyaluronan synthesis revealing the critical role of HAS2 in this process.
Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, via JH Dunant 5, 21100 Varese, Italy.
Davide
D
Vigetti
Anna
A
Genasetti
Evgenia
E
Karousou
Manuela
M
Viola
Paola
P
Moretto
Moira
M
Clerici
Sara
S
Deleonibus
Giancarlo
G
De Luca
Vincent C
VC
Hascall
Alberto
A
Passi
D002448:Cell Adhesion; D016207:Cytokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells; D014470:Umbilical Cord / Q000166:cytology
D016207:Cytokines; D018960:Hyaluronan Receptors; D053583:Interleukin-1beta; D016328:NF-kappa B; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases