2. Overview and significance of Immune-endocrine interactions in the regulation of Leydig cell function

3. Mitochondrial vs. Nuclear control of steroidogenesis Acute regulation at the level of substrate availability Chronic regulation at the level of gene transcription cAMP PKA + + testosterone + ROS cytokines - -

4. Steroidogenic machinery

5. Sites of immune inhibition ROS

6. Relevance to female reproduction? Normal physiological states: ovulation, menstruation, implantation, fetal-maternal interactions, parturition, and nursing all involve aspects of immune-endocrine cooperation LPS injection inhibits ovarian steroidogenesis

7. H 2 O 2 effects on luteal cells Behrman et al. have shown H 2 O 2 blocks cholesterol transfer inhibits 3  -HSD –Behrman HR, Aten RF. Endocrinology 1991;128(6):2958-66 Carlson et al. have shown H 2 O 2 causes lipid peroxidation –Carlson JC, et al. Free Radic Biol Med 1993;14(1):79-84 Reactive oxygen generated by leukocytes may contribute to luteolysis and initiate apoptosis

8. Sexual dichotomy of immune responses Females are more susceptible to autoimmune diseases than males Estradiol and prolactin are both immuno- stimulatory Testosterone is immuno-inhibitory

9. ConclusionsConclusions Inflammation and infection may contribute to, or cause decreased male reproductive function There is a push-pull system between the immune and endocrine systems –During times of sickness the immune system suppresses the reproductive system (testosterone production) –During times of normal health testosterone suppresses the immune response

10. Antechinus Stuartii victim of his own testosterone

11. NIH: HD25271 HD35544 Beth Nardulli Salil Ginde John Allen Thorsten Diemer John Choi Beth Nardulli Salil Ginde John Allen Thorsten Diemer John Choi Hales Lab Bruce Bosmann Barbara Clark Jim Ferguson Lester Lau Jean-Guy LeHoux Mark McLean Yossi Orly Keith Parker Anita Payne Richard Pestell Catherine Rivier Focko Rommerts Douglas Stocco Bruce Bosmann Barbara Clark Jim Ferguson Lester Lau Jean-Guy LeHoux Mark McLean Yossi Orly Keith Parker Anita Payne Richard Pestell Catherine Rivier Focko Rommerts Douglas Stocco collaborators Karen Held Hales

12. Immune-endocrine control of Leydig cells Cytokine control of steroidogenesis The role of AP-1 Navigation to other presentations Cytokine signaling