Autophagy, an evolutionally conserved homeostatic process for catabolizing cytoplasmic components, has been implicated in the elimination of intracellular pathogens during mammalian innate immune responses. However, the mechanisms underlying cytoplasmic infection-induced autophagy, and the role of autophagy in host survival against intracellular pathogens are unknown. Here we report that in drosophila, recognition of diaminopimelic acid-type peptidoglycans by the pattern recognition receptor PGRP-LE is crucial for the induction of autophagy, and that autophagy prevents the intracellular growth of Listeria monocytogenes and promotes host survival against this infection. Autophagy induction occurs independently of the Toll and IMD innate signaling pathways. These findings define a clear pathway leading from the intracellular pattern recognition receptors to the induction of autophagy to host defense.

In innate immunity, pattern recognition molecules recognize cell wall components of microorganisms and activate subsequent immune responses, such as the induction of antimicrobial peptides and melanization in Drosophila. The diaminopimelic acid (DAP)-type peptidoglycan potently activates imd-dependent induction of antibacterial peptides. Peptidoglycan recognition protein (PGRP) family members act as pattern recognition molecules. PGRP-LC loss-of-function mutations affect the imd-dependent induction of antibacterial peptides and resistance to Gramnegative bacteria, whereas PGRP-LE binds to the DAPtype peptidoglycan, and a gain-of-function mutation induces constitutive activation of both the imd pathway and melanization. Here, we generated PGRP-LE null mutants and report that PGRP-LE functions synergistically with PGRP-LC in producing resistance to Escherichia coli and Bacillus megaterium infections, which have the DAP-type peptidoglycan. Consistent with this, PGRP-LE acts both upstream and in parallel with PGRP-LC in the imd pathway, and is required for infection-dependent activation of melanization in Drosophila. A role for PGRP-LE in the epithelial induction of antimicrobial peptides is also suggested.

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Dienogest is a specific progesterone receptor agonist with potent oral endometrial activity and is used in the treatment of endometriosis. In this study, we examined the direct effects of dienogest on the proliferation of human endometrial epithelial cells using an immortalized cell line. 5-Bromo-2'-deoxyuridine incorporation into the cells was inhibited by dienogest and by progesterone (P(4)) in dose-dependent fashion at concentrations of 10(-8) mol/l or higher. To identify the target genes of dienogest and P(4), we screened the expression of 84 genes related to cell cycle regulation by real-time polymerase chain reaction after 6 h of treatment at a concentration of 10(-7) mol/l. Results showed that only cyclin D1 expression was significantly down-regulated, although expression of the other genes did not significantly change after dienogest or P(4) treatment compared with the control. In a time-course study during the first 24 h after drug treatment, dienogest and P(4) each produced a lasting decrease in the expression of cyclin D1 mRNA, followed by a decrease in cyclin E1 mRNA but not an increase in the expression of cell cycle inhibitor genes (p21, p27 and p53). These findings suggest that dienogest directly inhibits the proliferation of human endometrial epithelial cells with suppression of cyclin D1 gene expression.