Activated T lymphocytes accumulate early in atheroma formation and persist at

Activated T lymphocytes accumulate early in atheroma formation and persist at sites of lesion growth and rupture recommending that they could play a significant role in the pathogenesis of atherosclerosis. staining. ECs of microvessels within lesions expressed abundant I-TAC also. In vitro tests supported these outcomes and demonstrated that IL-1β TNF-α and Compact disc40 ligand potentiated IP-10 appearance from IFN-γ-stimulated ECs. In addition nitric oxide (NO) treatment decreased IFN-γ induction of IP-10. Our findings suggest that the differential expression of IP-10 Mig and I-TAC by atheroma-associated cells plays a role in the recruitment and retention of activated T lymphocytes observed within vascular wall lesions Dinaciclib during atherogenesis. Introduction Increasing evidence supports a crucial role for immunological and inflammatory responses in atherogenesis. The development of atherosclerotic lesions entails interactions between 4 major cell types: endothelial cells (ECs) easy muscle mass cells (SMCs) macrophages (M?) and lymphocytes (1 2 The role of T cells in atherogenesis remains unclear. However because activated T cells accumulate in atheroma – and Cryab Dinaciclib by virtue of their early appearance persistence and localization at sites of lesion growth and rupture – they may orchestrate important aspects of atherogenesis (3-7). Although atherosclerotic lesions contain both CD8+ and CD4+ T cells CD4+ memory (CD45RO+) T cells predominate (8). Previous studies have colocalized CD4+ T lymphocytes and IFN-γ within human and mouse atherosclerotic lesions (9) suggesting predominance of Th1 lymphocytes in atherogenesis (10). IFN-γ plays a critical role in modulating the cellular immune response by stimulating the production of proinflammatory cytokines adhesion molecules and MHC class II expression by ECs SMCs and M?. Moreover Gupta et al. have recently exhibited that apo E-knockout mice lacking the IFN-γ receptor developed fewer and smaller atherosclerotic lesions than did control mice suggesting that IFN-γ has proatherogenic properties (11). Despite increasing evidence for involvement of T lymphocytes in atherogenesis the mechanism of T-lymphocyte recruitment within the vascular atherosclerotic lesions remains incompletely defined. Lymphocyte recruitment into tissues is usually a multistep process including adhesion molecules and chemokines. Chemokines are secreted basic proteins (8-10 kDa) subdivided into 4 families based on the relative position of their cysteine residues (CC CXC C CXC3) (12). CXC chemokines further fall into 2 classes based on the presence or absence of a NH2-terminal sequence Glutamic acid-Leucine-Arginine (ELR). The Dinaciclib ELR-containing CXC chemokines such as IL-8 chemoattract neutrophils (13) whereas the non-ELR CXC chemokines chemoattract lymphocytes. Among the non-ELR CXC chemokines 3 of them – IP-10 (IFN-inducible protein 10) Mig (monokine induced by IFN-γ) and I-TAC (IFN-inducible T-cell α chemoattractant) – are IFN-γ inducible and potently chemoattract activated T lymphocytes (14-18). All 3 chemokines transmission through a common receptor CXCR3 expressed by memory (CD45RO+) T cells preferentially of the Th1 subset and by natural killer cells but not by monocytes or neutrophils (15 19 IP-10 has been found in numerous clinical conditions in which activated Th1 lymphocytes and IFN-γ expression were found such as psoriasis (23) tuberculoid leprosy (24) sarcoidosis (25) viral meningitis (26) and pulmonary tuberculosis (27). Mig was also found in psoriatic lesions by in situ hybridization (17). To date I-TAC has not been correlated with any human diseases. Chemokines such as IL-8 monocyte chemoattractant protein-1 (MCP-1) MCP-4 and RANTES have been shown to be expressed within atherosclerotic lesions in situ and by atheroma-associated cells in vitro (28-35). In addition in recent in vivo studies targeted disruption of the genes for MCP-1 CCR2 and CXCR2 significantly decreased atherosclerotic lesion formation and lipid deposition when the disrupted gene was bred or transferred into mouse strains prone to develop atherosclerotic-like lesions (36 37 29 Furthermore in these 3 in vivo studies the attenuated development of vascular lesions correlated with decreased M? accumulation in lesions demonstrating that chemokines play a critical role in monocyte/M? recruitment during atherogenesis. It is likely that chemokines also play a critical role in the recruitment and retention of activated T cells in atherosclerosis..