Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines

The atherosclerotic lesion contains large numbers of macrophages and T lymp hocytes. This suggests that a cellular immune response may take place in th e lesion, and oxidized lipoproteins, heat shock proteins, and micro-organis ms have been implied as candidate antigens. However, the effector mechanism s elicited by this response have been largely unclear. We have therefore an alyzed endarterectomy specimens by immunohistochemistry and reverse transcr iption-PCR to detect immune cytokines produced by immunocompetent cells of the advanced human plaque. The pro-inflammatory T cell cytokines, interleuk in-2 and interferon-gamma, were found in a large proportion of plaques (IL- 2 in 50% and interferon-gamma in 30% of plaques by immunohistochemistry and mRNA for both cytokines in 70% of plaques by PCR). In contrast, interleuki n-4 and interleukin-5 were rarely observed (both cytokines in 10% of plaque s by immunohistochemistry, mRNA for interleukin4 in 10% and for interleukin -5 in 40% by PCR). This demonstrates the presence of a predominantly pro-in flammatory, Th1-type T cell response in atherosclerosis. This conclusion wa s further supported by the expression of the pro-inflammatory cytokine, int erleukin-1 by plaque macrophages and endothelial cells. In addition, the ch emokine interleukin-8 and the macrophage differentiation-stimulating cytoki ne, granulocyte-monocyte colony stimulating factor, were observed in plaque tissues, suggesting that the micro-environment promotes monocyte recruitme nt and macrophage differentiation. Occasional eosinophils and B cells were, however observed, which is compatible with a microheterogeneity within the lesion. Finally, the anti-inflammatory and fibrogenic cytokines, transform ing growth factor-beta 1-3 and its carrier protein, latent TGF-beta binding protein, were found in large amounts in all plaques. Together, these resul ts show that a pro-inflammatory, Th1 type cellular immune response takes pl ace in the atherosclerotic plaque. The balance between pro-inflammatory and anti-inflammatory cytokines may be decisive for the progression of the les ion. (C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserve d.