Wesemann DR, Dong Y, O'Keefe GM, Nguyen VT, Benveniste EN.
Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages.
J Immunol. 2002 Sep 1;169(5):2354-60.
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In continuing their search for novel inhibitors of CD40 expression on macrophages/microglia, Wesemann and colleagues present data showing that SOCS-1 overexpression is able to mitigate IFN-gamma-induced CD40 expression in a macrophage cell line. It seems that this inhibition is accomplished at the protein, mRNA, and promoter activity levels. Investigation into upstream signaling events revealed that the STAT-1alpha and NF-kappaB pathways were both inhibited by SOCS-1 overexpression. Quite interestingly, exogenous application of TNF-alpha- which these authors show activates the NF-kappaB pathway but not the STAT-1alpha cascade- is not able to rescue SOCS-1 overexpression inhibition of IFN-gamma-induced CD40 expression. This result is important because it further confirms that activation of both pathways is required for efficient IFN-gamma induction of CD40. Given the importance of CD40-CD40L interactions in the pathogenesis of AD, this study is germane in that SOCS-1 and/or its downstream transduction molecules may be good pharmacotherapeutic targets for interrupting CD40 signaling. The authors themselves mention a study where SOCS-1 was shown to inhibit TNF-alpha signaling (Morita et al., 2000). This begs the question of how specific SOCS-1 is for down regulating CD40 expression as opposed to its effect on other TNFR/NGFR superfamily members such as TNFR-I, TNFR-II, and/or p75 NTR. Such future investigation would be important to give more insight into how viable SOCS-1 is as a pharmacotherapeutic target for disrupting CD40 signaling in AD.
Morita Y, Naka T, Kawazoe Y, Fujimoto M, Narazaki M, Nakagawa R, Fukuyama H, Nagata S, Kishimoto T.
Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor alpha-induced cell death in fibroblasts.
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5405-10.