Endogenous interleukin-1α promotes a proliferative and proinflammatory phenotype in human vascular smooth muscle cells

Abstract

Schultz K, Murthy V, Tatro JB, Beasley D. Endogenous interleukin-1␣ promotes a proliferative and proinflammatory phenotype in human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 292: H2927-H2934, 2007. First published February 9, 2007 doi:10.1152/ajpheart.00700.2006.-During vascular disease and following injury, vascular smooth muscle cells (VSMC) proliferate and produce inflammation-promoting cytokines and chemokines. Similar phenotypic changes can be elicited in vitro by activation of Toll-like receptors (TLR) within VSMC. TLR-activated VSMC also produce IL-1␣, but it is unknown whether endogenous IL-1␣ stimulates VSMC in an autocrine manner. Here we tested the hypothesis that endogenous IL-1␣ contributes to TLR-induced proliferation and chemokine release in human VSMC by using RNA interference to knock down IL-1␣ expression. Knockdown of IL-1␣ abolished TLR-induced proliferation and suppressed TLR4-induced release of monocyte chemoattractant protein-1 (MCP-1) by VSMC, indicating that endogenous IL-1␣ plays a crucial role in both responses. Serum, PDGF, FGF-2, and EGF each increased cellular IL-1␣ concentrations, and IL-1␣ knockdown inhibited serum-and PDGF-induced DNA synthesis, further indicating that endogenous IL-1␣ also contributed to VSMC responses to growth factors. IL-1 receptor antagonist, a competitive inhibitor of IL-1 receptor I (IL-1RI), also attenuated TLRinduced proliferation and both basal and TLR-induced MCP-1 expression, indicating at least a partial role of the IL-1RI in mediating these responses. The results support the hypothesis that autocrine actions of endogenous IL-1␣, mediated at least in part via IL-1RI signaling, contribute to a proproliferative and proinflammatory phenotypic shift in TLR-activated human VSMC, which might play a pathogenic role in vascular disorders. monocyte chemoattractant protein-1; cell proliferation; type I interleukin-1 receptor EXCESSIVE PROLIFERATION OF vascular smooth muscle cells (VSMC) is a prototypical response to vascular injury and is also a feature of early-stage atherogenesis. Such proliferative responses of VSMC may contribute to vascular repair in some cases, but they can also lead to restenosis when excessive (1). Another fundamental and dramatic change displayed by VSMC following either vascular injury or chronic exposure to intravascular lipids is their shift to a proinflammatory phenotype, characterized by the synthesis of proinflammatory cytokines and chemokines, including interleukin-1␣ (IL-1␣) and monocyte chemoattractant protein-1 (MCP-1) (7,9,22,29). The functions of endogenous VSMC-derived IL-1␣ in this context are unknown, but we have hypothesized that it may play an autocrine role in promoting VSMC proliferation, based on in vitro and in vivo lines of evidence. For example, in coronary bypass patients, IL-1␣ was found in spindle-shaped cells within saphenous vein grafts that had become stenotic but not in those that remained patent (5). Similarly, IL-1␣ mRNA was found in medial smooth muscle cells (SMC) within arterial ...

Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia

“…21,22 The present study demonstrated that inhibition of s-EH reduced circulating inflammatory mediators, including IL-1␣, IL-6, and murine IL-8-KC, all of which have been reported as being involved in the development of atherosclerosis. [23][24][25][26][27] Furthermore, the present data have demonstrated that s-EH inhibition decreased the expression of proinflammatory genes in arterial wall, such as VCAM-1 and ICAM-1, which are critical adhesion proteins playing an early and essential role in the pathogenesis of atherosclerosis. 28 The pathohistological examination also revealed a marked reduction of inflammatory cell infiltration and extracellular matrix destruction in the vascular wall in AR9276-treated mice, which was also accompanied by a reduction of proinflammatory mediators.…”

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

“…This 158 evidence raises questions about how TLR signaling alters the different compartments of blood vessels and the interaction between the layers of the vascular wall. Previous research has focused on TLR signaling in endothelial cells as well as immune cells that infiltrate the vascular wall (Yang et al, 2005a(Yang et al, ,b, 2006de Graaf et al, 2006;Schultz et al, 2007;Pryshchep et al, 2008;Zimmer et al, 2011;Liang et al, 2013). Currently, there is a growing interest in the adventitial compartment of blood vessels and in particular the adventitial fibroblast, which play an important role in regulating the structure and function of the vascular wall (Stenmark et al, 2013;El Kasmi et al, 2014).…”

“…Similarly, TLR4 deficiency improved indices of atherosclerosis in both ApoE- (Michelsen et al, 2004) and LDL receptordeficient mice (Ding et al, 2012). Moreover, TLR4 has an important role in the proatherogenic response of macrophages to oxidized LDL and lipid accumulation (Kazemi et al, 2005;Miller, 2005), proinflammatory and proliferative phenotype in vascular smooth muscle cells (de Graaf et al, 2006;Yang et al, 2005b;Schultz et al, 2007), and endothelial dysfunction (Yang et al, 2005a;Liang et al, 2013). On the other hand, the contribution of TLR5 to atherosclerosis is relatively sparse.…”

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

“…As a result, this promoted a HASMCs inflammatory phenotype and vascular remodeling [112]. In addition, in 2007, Schultz and colleagues [113], using human VSMCs cell cultures derived from digestion of human coronary artery or pulmonary artery, detected that autocrine actions of endogenous interleukin (IL)-1 α, mediated at least in part via IL-1RI signaling, contributed to a pro-proliferative and proinflammatory phenotypic shift in TLR-4-activated human VSMCs. As a consequence, they suggested a pathogenic role of TLR-4 pathway in vascular disorders.…”