The roles of IL-10 and IL-4 receptor signaling were evaluated in a murine model of Leishmania major infection. In previous studies the L. major substrain LV39 caused progressive, nonhealing lesions in BALB/c mice deficient for IL-4R α-chain (IL-4Rα), while substrain IR173 was highly controlled. To explore whether IL-10 is responsible for inducing susceptibility to LV39, wild-type and IL-4Rα−/− mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4Rα−/− mice were crossed with BALB/c IL-10−/− mice. In contrast to the lack of resistance conferred by IL-4Rα gene deletion, partial resistance to LV39 was conferred by IL-10 gene deletion or treatment of BALB/c mice with anti-IL-10R mAb. Lesion sizes and LV39 parasite numbers were further and dramatically reduced in both anti-IL-10R-treated IL-4Rα−/− mice and IL-4Rα × IL-10 double knockouts. Anti-IL-10R mAb treatment further suppressed parasite growth in IL-4Rα−/− mice infected with L. major IR173. Production of IFN-γ was only increased relative to wild-type or littermate controls in IL-4Rα−/− mice with complementary defects in IL-10. Comparisons of IFN-γ-treated infected macrophages in vitro indicated that LV39 required 25- to 500-fold greater concentrations of IFN-γ than IR173-infected macrophages to achieve a similar efficiency of parasite killing. These studies suggest that regardless of parasite substrain, IL-10 is as important as IL-4/IL-13 in promoting susceptibility to L. major and even more so for those substrains that are relatively resistant to IFN-γ mediated killing.

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Delta is a major transmembrane ligand for Notch receptor that mediates numerous cell fate decisions. The Notch signaling pathway has long been thought to be mono-directional, because ligands for Notch were generally believed to be unable to transmit signals into the cells expressing them. However, we showed here that Notch also supplies signals to neighboring mouse neural stem cells (NSCs). To investigate the Notch–Delta signaling pathway in a bi-directional manner, we analyzed functional roles of the intracellular domain of mouse Delta like protein 1 (Dll1IC). In developing mouse NSCs, Dll1IC, which is released from cell membrane by proteolysis, is present in the nucleus. Furthermore, we screened for transcription factors that bind to Dll1IC and demonstrated that Dll1IC binds specifically to transcription factors involved in TGF-β/Activin signaling—Smad2, Smad3 and Smad4—and enhances Smad-dependent transcription. In addition, the results of the present study indicated that over-expression of Dll1IC in embryonic carcinoma P19 cells induced neurons, and this induction was blocked by SB431542, which is a specific inhibitor of TGF-β/Activin signaling. These observations strongly suggested that Dll1IC mediates TGF-β/Activin signaling through binding to Smads and plays an important role for bi-directional Notch–Delta signaling pathway.