Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells.

Abstract

Muscle cell differentiation is characterized by the synthesis ofcontractile proteins, their organization in specialized structures, the synthesis of enzymes ofspecific metabolic pathways, and the inhibition ofcell proliferation (1). Activation ofmuscle-specific gene expression is coupled to withdrawal from the cell cycle; therefore, much interest has been focused on the role ofgrowth factors in the control ofmuscle differentiation (2-7). In skeletal muscle myoblasts, a reduction of growth factor concentration causes a stop of DNA synthesis, withdrawal from the cell cycle, expression of muscle-specific genes, and fusion ofthe myoblasts into multinucleated myotubes (7).For smooth muscle cells (SMC)', the process is less distinctive on the cellular level, since fusion never occurs . However, during the development of the arterial tree, the acquisition of differentiated features by SMC coincides with a decreased and/or arrested replicative activity (8). Moreover, a reduction of the concentration of serum added to SMC cultures leads to a partial reexpression of muscle-specific mRNAs (9) and ofthe smooth muscle-specific isoform of actin protein, a-SM actin (10,11). Similarly, an increase in serum concentration is followed by downregulation ofa-SM actin expression and induction ofcell proliferation (10-12). This establishes a negative relationship between exposure to growth factors and differentiation, but it is unclear to what extent growth-inhibitory macromolecules affect differentiation of SMC.Interferons (IFNs) are important inhibitors ofcell proliferation, and different types of IFNs may be involved in both paracrine and autocrine growth regulation (13). IFN-y is produced by activated T lymphocytes, and is released during the immune response and in inflammatory conditions (13,14). Arterial SMC respond to IFN-'r by expression of class II MHC genes such as HLA-DR (15). These genes are expressed by SMC in the vicinity ofT cell infiltrates in experimentally injured arteries

Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells.

“…151632 IFN-y also accentuates the usual "modulated" pattern of actin expression manifested by VSMCs in culture (a predominance of /3-and a-nonmuscle actin) by reducing expression of the a-smooth muscle actin isoform. 33 We report here that IFN-y also profoundly suppresses both basal and stimulated collagen gene expression by VSMCs. Taken together, our observations support the concept that a balance between cytokines or growth factors with opposing effects influences the phenotype of VSMCs within specific regions of the blood vessels.…”

“…For example, this lymphokine specifically induces the expression of major histocompatibility complex class II genes, is > 32 yet reduces expression of a-actin in this cell type. 33 To clarify the mechanism by which these cytokines and growth factors alter collagen metabolism in VSMCs, we measured steady-state mRNA levels by Northern analysis. IL-la and TGF-/3 increased mRNA encoding al(III) and a2(I) procollagens ( Figure 5).…”

Increased T-helper interferon-γ-secreting cells in obese children

“…Cell-culture studies have shown it to be a powerful growth inhibitor for endothelial cells and smooth muscle cells (SMCs) (16,17). In vivo studies in rats have shown that the proliferative response of SMCs after arterial injury is inhibited by IFN-g (18), which also inhibits smooth muscle contractility and collagen synthesis (17,19). It was therefore proposed that IFN-g-producing T cells could play an important role in plaque destabilization by reducing the fibrous cap (20).…”

“…IFN-g is an important immune-activating cytokine that can prime macrophages for activation and induce inflammatory responses such as those observed in delayed-type hypersensitivity and granulomatous lesions (15). Cell-culture studies have shown it to be a powerful growth inhibitor for endothelial cells and smooth muscle cells (SMCs) (16,17). In vivo studies in rats have shown that the proliferative response of SMCs after arterial injury is inhibited by IFN-g (18), which also inhibits smooth muscle contractility and collagen synthesis (17,19).…”

Interferon-γ Axis in Graft Arteriosclerosis

“…IFN-␥ was generally viewed as an antiproliferative cytokine for viral-infected cells, cancer cells, and primary cultured cells, including ECs and VSMCs. [95][96][97][98][99][100] However, there have been occasional reports that IFN-␥ can promote VSMC growth by potentiating growth factor signaling under certain in vitro conditions, such as serum deprivation. 40,[101][102][103][104] Similarly, IFN-␥ occasionally results in the proliferation of other mesenchymal cell types [105][106][107][108] and even ECs.…”