No abstract

The CIITA is a master regulator for MHC class II expression, but the signaling events that control CIITA expression remain poorly understood. In this study, we report that both constitutive and IFN-γ-inducible expression of CIITA in mouse bone marrow-derived dendritic cells (DC) and macrophages, respectively, are regulated by MAPK signals. In DC, the inhibitory effect of LPS on CIITA expression was prevented by MyD88 deficiency or pharmacological MAPK inhibitors specific for MEK (U0126) and p38 (SB203580), but not JNK (SP600125). In macrophages, LPS inhibited IFN-γ-inducible CIITA and MHC class II expression without affecting expression of IFN regulatory factor-1 and MHC class I. Blocking ERK and p38 by MAPK inhibitors not only rescued LPS-mediated inhibition, but also augmented IFN-γ induction of CIITA. Moreover, the induction of CIITA by IFN-γ was enhanced by overexpressing MAPK phosphatase-1 that inactivates MAPK. Conversely, CIITA expression was attenuated in the absence of MAPK phosphatase-1. The down-regulation of CIITA gene expression by ERK and p38 was at least partly due to decreased histone acetylation of the CIITA promoter. Our study indicates that both MAPK and phosphatase play an important role for CIITA regulation in DC and macrophages.

No abstract

Psoriasis is a common chronic and complex autoimmune inflammatory skin disorder. The histological characteristics of psoriasis are epidermal hyperplasia, mononuclear leukocyte infiltration into the dermis, and increased angiogenesis. However, the mechanisms involved in the pathogenesis of psoriasis remain unclear. Extracellular superoxide dismutase (EC-SOD) has antichemotactic activities. Because immune cell infiltration is seen in psoriatic lesions and psoriasis patients express low levels of EC-SOD, we hypothesized that the lack of EC-SOD induces more severe IL-23-mediated psoriasis-like skin inflammation. To test this hypothesis, we determined whether the loss of EC-SOD causes more severe IL-23-induced skin inflammation. Ear skin after IL-23 administration was thicker in EC-SOD knockout (KO) mice compared with wild-type mice. In addition, infiltration of CD4(+) T cells, macrophages, and dendritic cells (DCs) into IL-23 injection sites was more elevated in EC-SOD KO mice. The expression of proinflammatory cytokines and chemokines was also more elevated in EC-SOD KO mice, and EC-SOD KO DCs expressed a higher level of MHCII. Finally, EC-SOD transgenic mice showed much less severe IL-23-induced skin inflammation. Therefore, EC-SOD may inhibit IL-23-induced psoriasis-like inflammation through the inhibition of immune cell infiltration and immune responses. These results suggest that EC-SOD could be a possible candidate for management of psoriasis.

Therefore, patients with this variant may be treated with SOD3 as a therapeutic strategy to prevent or cure these diseases.

The class II transactivator (CIITA) is a key regulatory factor for MHC class II expression. Here, we demonstrate that PKCδ plays an important role in regulating IFN-γ-inducible CIITA gene expression in macrophages. Inhibition of PKCδ by either a PKCδ inhibitor or a dominant negative (DN) mutant form of PKCδ led to down-regulation of CIITA expression. The decrease in CIITA expression by PKCδ inhibition was in part due to the reduced recruitment of serine 727-phosphorylated Stat1 and histone acetyltransferases to the CIITA promoter. As a result, IFN-γ induced histone acetylation at the CIITA promoter is also compromised. However, inhibition of PKCδ did not affect IRF-1 expression or IRF-1 binding to the CIITA promoter. Therefore, we report, for the first time, that PKCδ is an essential signaling molecule to achieve the maximal expression of CIITA in response to IFN-γ in macrophages. In addition, although IRF-1 is a key transcription factor to activate the IFN-γ inducible CIITA promoter, the effect of PKCδ on CIITA expression is mediated primarily by serine phosphorylation of Stat1.

No abstract

We examined the beneficial effects of an active principle in kimchi, 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), on atherogenesis in apolipoprotein E knockout (apoE KO) mice. ApoE KO mice were fed an atherogenic diet containing 1% cholesterol (control group) with an intraperitoneal injection of chemically synthesized HDMPPA (10 mg/kg/day) (HDMPPA group) for 8 weeks. The aortic sinus atherosclerotic lesion size in the HDMPPA group (n = 10) was significantly smaller (control vs. HDMPPA, 280,790 vs. 165,409 microm(2), P < .001). The level of reactive oxygen species (ROS) in the HDMPPA group was lower by 14%, compared with the control group (P < .05). Aortic NADPH oxidase activity was significantly lower in the HDMPPA group than in the control group. HDMPPA suppressed the mRNA expression of p47phox and rac-1 of NADPH oxidase by 27.2% and 46.0%, respectively, compared with values of the control group. In conclusion, HDMPPA in kimchi may attenuate atherosclerosis in apoE KO mice through retardation of ROS generation via down-regulating the mRNA expression of p47phox and rac-1, which are the components of NADPH oxidase.