Adaptor protein Shc acts as an immune-regulator for the LPS-stimulated maturation of bone marrow-derived dendritic cells

We found that, in response to LPS, expression of Shc proteins was induced and that neutralization of Shc inhibited the LPS-induced transient phosphorylation of p52Shc on pTyr239/240 in DCs of Lewis (LEW; RT1l) rats. Moreover, the significantly enhanced expression of IL-10 and the surface level of costimulatory molecule CD80, as well as suppressed expression of IL-6 and IL-12 in the Shc-silenced DCs were also observed. Similar IκB phosphorylation occurred in Shc-silenced DCs primed by LPS, indicating Shc is not associated with NF-κB pathway. We further demonstrate that Shc blockade on LPS-treated DCs results in significant increase of the overall STAT3 phosphorylation and the relative levels of phospho-STAT3 in the nuclear fraction. STAT3 activation by LPS with or without Shc blockade was totally abolished by SU6656, a selective Src family kinases inhibitor, underscoring the critical role of Src-mediated activation.We conclude that Shc blockade in LPS-primed DC leads to the development of tolerogenic DC via Src-dependent STAT3 activation and that adaptor protein Shc might play a pivotal role in mediating immunogenic and tolerogenic properties of DCs.Dendritic cells (DCs) are the most important APC that play a crucial role in bridging innate resistance and adaptive immunity [1,2]. Immature DCs reside in peripheral tissues, where they release soluble mediators (cytokines, chemokines and IFNs) that participate in innate inflammatory responses during infection [2,3]. Upon capturing antigens, DCs migrate to the lymph nodes and present processed antigenic epitopes to T cells, resulting in their activation and further expansion [4,5]. A variety of signals induce DC maturation. Mature DCs express high levels of antigen presenting and co-stimulatory molecules and certain cytokines critical for the nature of the T cell response. For instance, Th1-type T cell responses need inflammatory IL-12 produced by DCs. Conversely, DCs can also produce anti-inflammatory cytokines, such as