| The latent transcription factor Stat3 is the major positive regulator of acute phase response genes in the liver. Two isoforms of Stat3 are generated by alternative splicing, Stat3alpha and Stat3beta. The beta isoform lacks the C-terminal transactivation domain but otherwise retains all of the functions of the alpha isoform, including dimerization, DNA binding and synergistic interaction with other transcription factors such as AP1. It was previously shown that Stat3beta-deficient knock-in mice exhibited constitutively elevated expression of systemic inflammatory genes and were also hyperresponsive to bacterial lipopolysaccharide. Expression and regulation of Stat3alpha were unperturbed in the Stat3beta-deficient animals. Thus, Stat3beta acts as a global negative modulator of the acute phase response.;A number of epidemiological studies have shown positive correlations between systemic inflammatory markers and atherosclerosis suggesting that Stat3beta deficiency would exacerbate the development of atherosclerosis. To test this we have bred the Stat3beta null mice with ApoE-deficient C57BL/6 mice. No differences were found between the serum cholesterol levels of ApoE-/-Stat3beta+/+ and ApoE-I-Stat3beta-/- mice. In contrast, we found that Stat3beta deficiency significantly accelerated the progression of atherosclerosis in the ApoE deficient model. Moreover, the effect of Stat3beta deficiency was more readily observed in female than in male mice, but could be unmasked in male mice by feeding a high- fat diet. The cellular composition of aortic root plaques and whole aorta were analyzed by morphometric methods and a quantitative PCR-based assay. No increase was observed in the representation of macrophages in plaques or aortas from the double mutant mice. The proportion of Th17 cells, however, as revealed by the transcription factor RORgammat, was significantly elevated in aortas from ApoE-/-Stat3beta-/- animals. Th17 cells produce IL-17, which is pro-atherogenic. Moreover, as the expression of RORgammat is controlled directly by Stat3, our findings strongly suggest that the increased number of Th17 cells in aortas from ApoE-/- Stat3beta-/- mice are a consequence of the unopposed action of Stat3alpha. |
