. Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages. J Immunol. 2002 Sep 1;169(5):2354-60. PubMed.

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  1. 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.

    References:

    . 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. PubMed.