OR25-4 Corticotropin Releasing Factor Receptor 2 Mediates Sex-specific Cellular Stress Responses

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR25-Signaling Originating from Membrane Receptors
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:00 PM
Room 133 (Moscone Center)
Pallavi Mhaske*1, Eric P Kubat1, Shilpi Mahajan1, Min Liao1, Peter T Ohara2 and Aditi Bhargava1
1UCSF, San Francisco, CA, 2UCSF
The classic “flight or fight” stress response involves neurohormonal activation of the corticotropin-releasing factor (CRF) system via the hypothalamic-adrenal-pituitary axis. Females suffer twice as much as males from stress-related disorders, where inflammation and the CRF system are involved. However, the molecular mechanism by which the CRF system mediates its effect on cellular stress pathways remains to be elucidated. Using an acute model of inflammation (pancreatitis), we show that CRF receptor2 (CRF2) is a key mediator of the endoplasmic reticulum (ER) stress response pathway. Pancreatitis was induced in wild type (WT) and CRF2-/- (KO) mice with 6 one-hourly injections of caerulein. Ultra structural cellular changes were identified using electron microscopy. Post inflammation, male and female WT mice displayed de novo induction of Ucn1 in exocrine acinar cells that was not observed in KO of either sex. Interestingly, baseline Ucn1 expression did not change in the endocrine islet cells even after inflammation. Caerulein-treated pancreatic acinar cells (AR42J) also showed de novo Ucn1 mRNA induction.  Furthermore, amylase release, an early pathogenic marker of pancreatitis, was decreased in vivo and in AR42J cells after Ucn1 treatment. Histologic severity scores were increased over WT in male and female KO mice. Exogenous Ucn1 decreased necrosis, vacuolization, and zymogen degranulation in male WT and KO mice. Conversely, in female WT and KO mice, Ucn1 further accentuated histologic damage. Electron microscopy showed gross disruption of the acinar cell rough ER in KO mice, which was accompanied by activation of the unfolded protein response to inhibit protein translation. Increased ubiquitinated proteins and pERK levels, and decreased peIF2α reflected ER stress response in WT and KO mice of both sexes. Vimentin, a perinuclear cytoskeleton protein important for cell integrity, found to interact with CRF2, was mis-targeted in KO mice during pancreatitis. Exogenous Ucn1 rescued many aspects of ER stress response in male, but not in female WT and KO mice. We conclude that reduced expression of CRF2 leads to increased susceptibility to inflammation in both sexes, but the resultant cellular stress pathways involved in coping and resolution are distinct in each sex. We provide evidence that suggests that the reason for clinical CRF-based treatment failures may not lie in the therapeutics themselves, but in the sex-specific response to the therapeutics.

Nothing to Disclose: PM, EPK, SM, ML, PTO, AB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH/NIDDK - DK080787 to AB