Interleukin-10 attenuates the response to vascular injury.
ABSTRACT The inflammatory response to vascular injury is characterized by expression of cytokines, growth factors, and chemokines that conspire to promote vessel remodeling and intimal hyperplasia (IH). Interleukin-10 (IL-10) is a multifunctional cytokine that has several anti-inflammatory properties in vitro. Few studies have evaluated the effects of IL-10 in experimental atherosclerosis. The purpose of the present study was to determine the influence of IL-10 on vascular inflammation and IH following mechanical injury.
Wire carotid injury was performed in wild-type (WT) mice with and without IL-10 treatment. Immunohistochemistry, PCR, and ELISA assays were used to examine vessel production of basic fibroblast growth factor (bFGF), monocyte chemotactic protein-1 (MCP-1), and nuclear factor kappa B (NFkappaB). Vessels were morphometrically analyzed for IH.
Carotid injury induced early expression of MCP-1 and bFGF that was abrogated in mice treated with IL-10. Similarly, injury-induced expression of NFkappaB message and protein was attenuated in mice receiving exogenous IL-10. Compared to untreated mice, IL-10 markedly decreased levels of IH. Interestingly, carotid injury in IL-10-deficient mice resulted in an augmented IH response compared to injured WT mice.
In an in vivo model of direct vascular injury, IL-10 decreased expression of the pro-inflammatory transcription factor, NFkappaB, and the mitogenic chemokine and growth factor, MCP-1 and bFGF, respectively. These observations were associated with IL-10-induced attenuation of IH. Furthermore, endogenous IL-10 appeared to suppress the injury response. In conclusion, exogenously delivered IL-10 may represent a clinically relevant anti-inflammatory strategy for post-injury intimal hyperplasia.
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ABSTRACT: A degradable, polar, hydrophobic, ionic polyurethane (D-PHI), with physical properties comparable to those of peripheral arterial vascular tissue, was evaluated for monocyte interactions with two different physical forms: two-dimensional films and three-dimensional porous scaffolds. Monocytes, isolated from human whole blood, were seeded onto D-PHI films and scaffolds, and differentiated to monocyte-derived macrophages (MDM) for up to 28 days. The effect of surface structure on the MDM phenotype was assessed by assaying: cell attachment (DNA), activation (intracellular protein expression, esterase and acid phosphatase (AP) activity) as well as pro- and anti-inflammatory cytokines (TNF-α and IL-10, respectively). The cells on scaffolds exhibited an initial peak in total protein synthesized per DNA at 3 days; however, both substrates generated similar protein levels per DNA at all other time points. While scaffolds generated more esterase and AP per cell than for films, the cells on films expressed significantly more of these two proteins relative to their total protein produced. At day 7 (acute phase of monocyte activation), cells on films were significantly more activated than monocytes on the scaffolds as assessed by cell morphology and tumor necrosis factor-α and interleukin-10 levels. Histological analysis of scaffolds showed that cells were able to migrate throughout the three-dimensional matrix. By inducing a low inflammatory, high wound-healing phenotype monocyte, the negative effects of the foreign body reaction in vivo may be controlled in a manner possible to direct the vascular tissue cells into the appropriate functional phenotypes necessary for successful tissue engineering.Acta biomaterialia 01/2011; 7(1):115-22. DOI:10.1016/j.actbio.2010.08.014 · 5.68 Impact Factor
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ABSTRACT: Adaptive and innate immune responses play a critical role in the protection against extracellular or intracellular pathogens. The function of these two types of immune responses is coordinated by CD4+ T-helper (Th) cells. Depending on the cytokine environment, Th progenitor (Thp) cells differentiate into three functionally different effector subsets. T-helper-1 (Th1) cells which mediate cell-mediated immunity, T-helper-2 (Th2) which orchestrates humoral immunity and T-helper-17 (Th17) cells key players in autoimmunity response. Cytokine induced transcription factors that are differentially expressed in Th cells are required for the development and commitment to a specific Th lineage. The population of Th2 cells can be subdivided in subpopulations depending on the level of a cytokine and the subsets of cytokines they produce. Very limited information is available about the regulation of cytokine production in this array of Th2 cells. We have recently identified the ETS family transcription factor PU.1 as regulating heterogeneity in Th2 populations. To define additional factors that might contribute to Th2 heterogeneity, we examined the PU.1 interacting protein IFN-regulatory factor (IRF)-4, a transcription factor expressed in lymphocytes and macrophages. When Th2 cells are separated based on levels of IL-10 secretion, IRF4 expression segregates into the subset of Th2 cells expressing high levels of IL-10. To investigate the role of IRF4 in cytokine heterogeneity, Th2 cells were infected with retrovirus expressing IRF4. The cells overexpressing IRF4 secreted significantly higher levels of IL-10 and IL-4 compared to cells infected with a control vector at the same time the level of IL-9 decreases. To understand the mechanism by which IRF4 regulates IL-10 expression in various Th2 cell subpopulations we used co-immunoprecipitation assays to determine transcription factors that interact with IRF4. Our data shows that PU.1, IRF4 and NFATc2 form a complex in Th2 nuclear extract. We also demonstrated by ChIP assay that IRF4 directly binds the Il10 and Il4 loci in a time dependent manner. The role of these protein-protein and protein-DNA complexes and their contribution towards Th2 heterogeneity will be further defined. Understanding the regulation of the anti-inflammatory cytokine IL-10 in Th2 cells may give us a tool to control inflammation.
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ABSTRACT: The cellular and extracellular matrix accumulations that comprise the lesions of atherosclerosis are driven by local release of cytokines at sites of predilection for lesion formation, and by the specific attraction and activation of cells expressing receptors for these cytokines. Although cytokines were originally characterized for their potent effects on immune and inflammatory cells, they also promote endothelial cell dysfunction and alter smooth muscle cell (SMC) phenotype and function, which can contribute to or retard vascular pathologies. This review summarizes in vivo studies that have characterized endothelial- and smooth muscle-specific effects of altering cytokine signaling in vascular disease. Although multiple reports have identified cytokines as pivotal players in endothelial and SMC responses in vascular disease, they also have highlighted the need to delineate the critical genes and specific cellular functions regulated by individual cytokine signaling pathways.The Journal of Lipid Research 07/2005; 46(6):1081-92. DOI:10.1194/jlr.R500004-JLR200 · 4.73 Impact Factor