Survival and function of human thymic dendritic cells are dependent on autocrine Hedgehog signaling

Abstract

The Hedgehog (Hh) family of signaling molecules functions in the development of numerous tissues during embryogenesis and has also been involved in adult self-renewing tissues. Recent results have demonstrated that the different components of the Hh signaling pathway are expressed in the human thymus. In this study, we investigate whether thymic dendritic cells (DCs) are cell targets for Hh signaling. Both components of the Hh receptor, Patched and Smoothened, as well as other Hh-binding proteins with modulating functions, are expressed by human thymic DCs. The expression of Gli1, Gli2, and Gli3 transcription factors suggests that the Hh signaling pathway is active in thymic DCs, and approximately one-half of thymic DCs produces Sonic Hh (Shh). The culture of thymic DCs with Shh protects them from apoptosis [similarly to CD40 ligand (CD40L)], and these antiapoptotic effects are related to an up-regulation of Bcl-2 and Bcl-X(L) protein expression. The addition of the Hh pathway inhibitor, cyclopamine, decreases DC viability and impairs their allostimulatory function in vitro. In addition, the blockade of the Hh signaling pathway by cyclopamine treatment abrogates the up-regulation of HLA-DR, CD86, CD80, and CD83 expression induced by CD40L on thymic DCs. Finally, we also show that after activation with CD40L thymic DCs down-regulate the expression of Hh receptor components as well as Shh production. Taken together, these results suggest that the survival and function of thymic DCs are regulated by an autocrine Hh signaling.

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A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance

“…[32][33][34][35][36] Additionally, the biological functions of autocrine Hh signaling have also been demonstrated in morphogenesis, pathophysiologic processes, and tumorigenesis. [37][38][39][40] However, autocrine Hh signaling in tumors was demonstrated in experiments that showed the inhibition of tumor growth via the Hh ligand-neutralizing antibody, 41,42 treatment with cyclopamine, 43 or RNA interference-mediated knockdown of SMO or GLI1. 44 Autocrine Hh ligand has not directly been shown to activate the Hh signaling pathway.…”

The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

“…Hedgehog (Hh) 3 proteins secreted by the thymus stroma and the CD4 ϩ CD8 ϩ double positive (DP) thymocytes have important regulatory functions in both mouse thymus (3)(4)(5)(6)(7)(8)(9)(10)(11) and human thymus (12,13). The Hh family of secreted signaling proteins is essential for embryonic development and homeostasis of adult renewable tissues (14 -17), and inappropriate Hh pathway activation is involved in many cancers (18,19).…”