IP-10/CXCR3 Axis Promotes the Proliferation of Vascular Smooth Muscle Cells through ERK1/2/CREB Signaling Pathway

Abstract

Excessive proliferation of vascular smooth muscle cells is one of the main pathological processes leading to atherosclerosis and intimal hyperplasia after vascular interventional therapy. Our previous study has shown that interferon-γ inducible protein-10 contributes to the proliferation of vascular smooth muscle cell. However, the underlying mechanisms remain unclear. Extracellular signal-regulated kinase 1/2, serine/threonine kinase Akt, and cAMP response element binding protein are signaling pathways, which are considered to play important roles in the processes of vascular smooth muscle cell proliferation. Moreover, chemokine receptor 3 and Toll-like receptor 4 are potential receptors of inducible protein-10 in this process. In the present study, IP-10 was found to directly induce vascular smooth muscle cell proliferation, and exposure to inducible protein-10 activated extracellular signal-regulated kinase 1/2, serine/threonine kinase, and cAMP response element binding protein signaling. Inhibitor of extracellular signal-regulated kinase 1/2, rather than inhibitor of serine/threonine kinase, inhibited the phosphorylation of cAMP response element binding protein and reduced inducible protein-10-stimulated vascular smooth muscle cell proliferation. Knockdown of cAMP response element binding protein by siRNA inhibited inducible protein-10-induced vascular smooth muscle cell proliferation. Moreover, anti-CXCR3 IgG, instead of anti-Toll-like receptor 4 IgG, reduced inducible protein-10-induced vascular smooth muscle cell proliferation and inducible protein-10-stimulated extracellular signal-regulated kinase 1/2 and cAMP response element binding protein activation. Together, these results indicate that inducible protein-10 promotes vascular smooth muscle cell proliferation via chemokine receptor 3 and activation of extracellular signal-regulated kinase 1/2 inducible protein-10-induced vascular smooth muscle cell proliferation. These data provide important targets for future studies to modulate atherosclerosis and restenosis after vascular interventional therapy.

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

“…39,40 Although the importance of CXCR3 in AML is not fully understood, Manuel Ramírez 41 reported that CXCL10/CXCR3 signaling plays an important role in the relapse of childhood acute lymphoblastic leukemia by inducing chemotaxis and diminishing chemotherapyrelated apoptosis. In line with previous reports showing that the CXCL10/CXCR3 axis activates MEK and ERK signaling in several cancer types, [42][43][44] our results demonstrated that ERK signaling was modulated by TKI-induced expression of CXCR3, which could be abrogated by GSI or CXCR3-specific inhibitors in FLT3/ITD + AML cells. This phenomenon is consistent with the observation that ERK signaling can be reactivated in FLT3/ITD + AML cells treated with TKIs, 8 and it supports the notion that CXCR3 is, at least partially, responsible for the TKI-induced changes in signaling (Fig.…”

Age‐related decline of interferon‐gamma responses in macrophage impairs satellite cell proliferation and regeneration

“…43 Recently, a series of studies showed that CXCL10 also could play roles in regulating cell proliferation, apoptosis, differentiation, and angiogenesis. [24][25][26][27] Our finding that expression of CXCL10 was accompanied by an increase of IFN-γ at the late stage after injury, while the inflammatory cells were recruited from circulation mainly at the early stage after injury, hints a novel role of CXCL10 in skeletal muscle repair. We found that MuSCs also expressed the receptor of CXCL10 and CXCR3.…”

“…Despite its chemotactic nature, CXCL10 is also reported to be a cytokine associated with cell proliferation, apoptosis, differentiation, and angiogenesis. [24][25][26][27] The receptor of CXCL10 is CXCR3, a G protein-coupled receptor expressed mainly in immune cells and other somatic cells. In uninjured young muscle, CXCR3 was expressed mostly in CD45 À CD31 À α7integrin + MuSCs (75.7%) as assessed by flow cytometry.…”

Parkinson’s disease: a systemic inflammatory disease accompanied by bacterial inflammagens

“…The subsequent platelet pathology, together with other changes in the haematological system such as anomalous fibrin(ogen) protein structure (discussed below) and RBC eryptosis (previously noted (Pretorius et al, 2018c)), all point to inflammation profile of systemic change. Here, the inflammatory molecules in our panel that showed the most significance in PD, and particularly IL-1a, IL-1β, IL-17A, and TNF-a are all known to be dysregulated in cardiovascular disease and their presence in circulation might be linked to atherosclerosis (Libby, 2017;Wang et al, 2017).…”