LXR activation reduces proinflammatory cytokine expression in human CD4-positive lymphocytes.

BACKGROUND: CD4-positive lymphocytes, the major T-cell population in human atheroma, mainly secrete Th-1-type proinflammatory cytokines, like interferon (IFN)gamma, tumor necrosis factor (TNF)alpha, and interleukin (IL)-2, thus promoting atherogenesis. Recent data suggest that the nuclear transcription factors liver X receptor-alpha and liver X receptor-beta (LXRalpha and LXRbeta) limit plaque formation in animal models by modulating macrophage function. Still, the role of LXRs in CD4-positive lymphocytes is currently unexplored. METHODS AND RESULTS: Human CD4-positive lymphocytes express LXRalpha and LXRbeta mRNA and protein. Activation of CD4-positive cells by anti-CD3 mAbs, anti-CD3/CD28 mAbs, as well as PMA/ionomycin significantly increased Th1-cytokine mRNA and protein expression. Treatment with the LXR activator T0901317 reduced this increase of IFNgamma, TNFalpha, and IL-2 in a concentration-dependent manner with a maximum at 1 micromol/L T0901317. Transient transfection assays revealed an inhibition of IFNgamma promoter activity by T0901317 as the underlying molecular mechanism. Such anti-inflammatory actions were also evident in cell-cell interactions with medium conditioned by T0901317-treated CD4-positive cells attenuating human monocyte CD64 expression. CONCLUSIONS: Human CD4-positive lymphocytes express both LXRalpha and LXRbeta, and LXR activation can reduce Th-1 cytokine expression in these cells. These data provide new insight how LXR activators might modulate the inflammatory process in atherogenesis and as such influence lesion development.

PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis.

Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-gamma, represent a critical step in atherogenesis and arteriosclerosis. IFNgamma pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFNgamma signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPARalpha and PPARgamma mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFNgamma protein secretion from 0 to 504+/-168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPARalpha (WY14643 or fenofibrate) or PPARgamma (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFNgamma secretion in a concentration-dependent manner. PPAR activators also inhibited TNFalpha and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPARalpha and PPARgamma in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNgamma, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.

Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model.

In septic shock, tissue factor (TF) activates blood coagulation, and cytokines and chemokines orchestrate an inflammatory response. In this study, the role of Egr-1 in lipopolysaccharide (LPS) induction of TF and inflammatory mediators in vivo was evaluated using Egr-1(+/+) and Egr-1(-/-) mice. Administration of LPS transiently increased the steady-state levels of Egr-1 mRNA in the kidneys and lungs of Egr-1(+/+) mice with maximal induction at one hour. Egr-1 was expressed in epithelial cells in the kidneys and lungs in untreated and LPS-treated mice. LPS induction of monocyte chemoattractant protein mRNA in the kidneys and lungs of Egr-1(-/-) mice was not affected at 3 hours, but its expression was significantly reduced at 8 hours compared with the expression observed in Egr-1(+/+) mice. Similarly, LPS induction of TF mRNA expression in the kidneys and lungs at 8 hours was reduced in Egr-1(-/-) mice. However, Egr-1 deficiency did not affect plasma levels of tumor necrosis factor alpha in endotoxemic mice. Moreover, Egr-1(+/+) and Egr-1(-/-) mice exhibited similar survival times in a model of acute endotoxemia. These data indicate that Egr-1 does not contribute to the early inflammatory response in the kidneys and lungs or the early systemic inflammatory response in endotoxemic mice. However, Egr-1 does contribute to the sustained expression of inflammatory mediators and to the maximal expression of TF at 8 hours in the kidneys and lungs.