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Control of vascular smooth-muscle cell growth by macrophage-colony-stimulating factor.

ABSTRACT: Since in several vascular diseases abnormal vascular smooth-muscle cell (VSMC) proliferation is often associated with the presence of macrophages, we examined whether macrophage-colony-stimulating factor (M-CSF) might play a role in the control of VSMC growth. VSMCs were isolated from rat aorta and maintained in culture. Using a bioassay, a macrophage-colony-stimulating activity was detected in the serum-free supernatant of VSMCs, which could be inhibited by the addition of specific anti-M-CSF antibodies. The presence of M-CSF receptor protein and of M-CSF and M-CSF receptor gene transcripts was demonstrated by immunocytochemistry, using a specific anti-c-Fms antibody and Northern blot analysis respectively. [3H]Thymidine incorporation was measured following the addition to quiescent VSMCs of various dilutions of L929 cell supernatant (as a source of M-CSF) or of recombinant M-CSF. Both exogenous M-CSF and serum-free VSMC conditioned medium promoted DNA synthesis in a concentration-dependent manner, and this effect could be abrogated by the presence of a specific anti-M-CSF antibody. Under similar experimental conditions, L929 cell supernatant modulated proto-oncogene expression, as assessed by Northern blot analysis of c-fos, c-myc, egr-1 and junB. It was further demonstrated that M-CSF could act in synergy with thrombin, platelet-derived growth factor or basic fibroblast growth factor in promoting VSMC DNA synthesis. These results support the hypothesis that M-CSF affects the growth of cultured rat VSMCs through paracrine/autocrine mechanisms. Its effects at both the macrophage and the VSMC level confer to M-CSF a central role in the development of vascular lesions that occurs during atherosclerotic progression.

SUBMITTER: Herembert T

PROVIDER: S-EPMC1218536 | biostudies-other | 1997 Jul

REPOSITORIES: biostudies-other

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Project description:Heat-killed (HK) Mycobacterium obuense (NCTC13365) is currently being evaluated in the clinic as an immunotherapeutic agent for cancer treatment. Yet, the molecular underpinnings underlying immunomodulatory properties of HK M. obuense are still largely undefined. To fill this void, we sought to perform immunophenotyping, chemokine/cytokine release analysis and genome-wide characterization of monocyte-derived macrophages (MDM) in which monocytes were originally isolated from healthy donors and differentiated by HK M. obuense (Mob-MDM) relative to macrophage colony-stimulating factor (M-MDM) and granulocyte/macrophage colony-stimulating factor (GM-MDM). Immunophenotyping and cytokine release analysis revealed downregulated surface expression of CD36, decreased spontaneous release of CCL2 and increased spontaneous secretion of CCL5, CXCL8/IL-8, IL-6, and TNF-? in Mob-MDM relative to M-MDM and GM-MDM. Analysis of cytostatic activity showed that Mob-MDM exhibited similar growth inhibitory effects on immortalized and malignant epithelial cells compared with GM-MDM but at an elevated rate relative to M-MDM. To understand global cues in Mob-MDM, we performed comparative RNA-sequencing (RNA-Seq) analysis of Mob-MDM relative to GM-MDM and M-MDM (n?=?4 donors). Clustering analysis underscored expression profiles (n?=?256) that were significantly modulated in Mob-MDM versus both M-MDM and GM-MDM including, among others, chemokines/cytokines and their receptors, enzymes and transcriptions factors. Topological functional analysis of these profiles identified pathways and gene sets linked to Mob-MDM phenotype including nitric oxide production, acute phase response signaling and microbe recognition pathways as well as signaling cues mediated by the proinflammatory cytokine, interferon-gamma, and the intracellular pattern recognition receptor, nucleotide-binding oligomerization domain-containing protein 2. Taken together, our study highlights molecular immune phenotypes and global signaling cues in Mob-MDM that may underlie immunomodulatory properties of HK M. obuense. Such properties could be of valuable use in immunotherapy approaches such as adoptive cell therapy against cancer.

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Control of vascular smooth-muscle cell growth by macrophage-colony-stimulating factor.

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