Regulation of CCL5 Expression in Smooth Muscle Cells Following Arterial Injury

Abstract

Chemokines play a crucial role in inflammation and in the pathophysiology of atherosclerosis by recruiting inflammatory immune cells to the endothelium. Chemokine CCL5 has been shown to be involved in atherosclerosis progression. However, little is known about how CCL5 is regulated in vascular smooth muscle cells. In this study we report that CCL5 mRNA expression was induced and peaked in aorta at day 7 and then declined after balloon artery injury, whereas IP-10 and MCP-1 mRNA expression were induced and peaked at day 3 and then rapidly declined.The expression of CCL5 receptors (CCR1, 3 & 5) were also rapidly induced and then declined except CCR5 which expression was still relatively high at day 14 after balloon injury. In rat smooth muscle cells (SMCs), similar as in aorta CCL5 mRNA expression was induced and kept increasing after LPS plus IFN-gamma stimulation, whereas IP-10 mRNA expression was rapidly induced and then declined. Our data further indicate that induction of CCL5 expression in SMCs was mediated by IRF-1 via binding to the IRF-1 response element in CCL5 promoter. Moreover, p38 MAPK was involved in suppression of CCL5 and IP-10 expression in SMCs through common upstream molecule MKK3. The downstream molecule MK2 was required for p38-mediated CCL5 but not IP-10 inhibition. Our findings indicate that CCL5 induction in aorta and SMCs is mediated by IRF-1 while activation of p38 MAPK signaling inhibits CCL5 and IP-10 expression. Methods targeting MK2 expression could be used to selectively regulate CCL5 but not IP-10 expression in SMCs.

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

“…We have previously reported that IRF-1 was key not only in driving steroid-resistant genes in ASM cells (25) but also in impairing ASM sensitivity to GC by reducing GRa transactivation function (32). Whether IRF-1 plays a role in the currently investigated GC chemokines in GCresistant conditions has not been investigated, although limited evidence indicates a role of IRF-1 in CCL5 expression in vascular smooth muscle (42) and bronchial epithelial cells (43). Our silencing experiments confirmed the key role of IRF-1 in ASM cells in driving the expression of GC-resistant chemokines via transcriptional (CCL5) and posttranscriptional mechanisms (CX3CL1).…”

Sphingosine Kinase 1 Regulates Tumor Necrosis Factor-mediated RANTES Induction through p38 Mitogen-activated Protein Kinase but Independently of Nuclear Factor κB Activation

“…The p38 MAPK pathway is a well known component of TNF signaling (46,47) and can also be regulated by SK1 (48 -50). Furthermore, this pathway can also affect chemokine expression, although the effects on RANTES vary depending on the cell type and stimulus (34,51,52). Consequently, as a first step, the role of p38 MAPK in RANTES regulation was determined utilizing the p38 MAPK inhibitor BIRB 796 (53).…”

“…In the TNF response, many transcription factors have been implicated in RANTES induction including NF-B and interferon regulatory factor 1 (29,30), and activator protein 1 and NF-AT in airway epithelial and smooth muscle cells, respectively (31). Moreover, upstream of transcription factors, other signaling cascades have been implicated in RANTES regulation such as JNK (32), ERK (33), and p38 MAPK (34). More recently, our group identified sphingolipids as regulators of RANTES through the acid sphingomyelinase/ acid ceramidase pathway (16).…”

Chemokine Ligand 5 (CCL5) Derived from Endothelial Colony-Forming Cells (ECFCs) Mediates Recruitment of Smooth Muscle Progenitor Cells (SPCs) toward Critical Vascular Locations in Moyamoya Disease

“…CCL5 is also known to be involved in the progression of atherosclerotic plaques [27]. CCL5 belongs to the CC chemokine family which also includes CCL2.…”

“…CCL2 was also one of the cytokines elevated in the serum of MMD patients [7]. CCL5 has been associated with the progression of atherosclerosis, mediating smooth muscle cell activation and macrophage recruitment [27]. Polymorphisms in the CCL5 gene were associated with stroke risks [28, 29].…”