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Title: Effects of IL8 and immune cells on the regulation of luteal progesterone secretion

item TALBOTT, HEATHER - Nebraska Medical Center
item DELANEY, ABIGAIL - Nebraska Medical Center
item ZHANG, PAN - Nebraska Medical Center
item YU, YANGSHENG - Nebraska Medical Center
item Cushman, Robert - Bob
item CUPP, ANDREA - University Of Nebraska
item HOU, XIAOYING - Nebraska Medical Center
item DAVIS, JOHN - Nebraska Medical Center

Submitted to: Reproduction
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/31/2014
Publication Date: 6/1/2014
Publication URL:
Citation: Talbott, H., Delaney, A., Zhang, P., Yu, Y., Cushman, R.A., Cupp, A.S., Hou, X., Davis, J.S. 2014. Effects of IL8 and immune cells on the regulation of luteal progesterone secretion. Reproduction. 148:21-31.

Interpretive Summary: The ovarian corpus luteum secretes the steroid hormone progesterone that is responsible for maintaining pregnancy in mammalian females. The corpus luteum must regress completely at the end of an infertile estrous cycle to initiate a new follicular phase and opportunity to become pregnant. In repeat breeder cows that fail to become pregnant during multiple estrous cycles, improper regression of the corpus luteum results in elevated progesterone concentrations during estrus and prolonged inter-estrus intervals due to delayed ovulation of the next follicle. Irregular estrous cycles result in decreased fertility when the inter-estrus interval prior to breeding exceeds 22 days, most likely due to ovulation of an egg with poor quality because of the delay in ovulation. Proper activation of a local immune response in the corpus luteum is critical for complete regression of the corpus luteum to initiate a new follicular phase at the optimal time without elevated progesterone concentrations. A series of experiments were performed to determine the timing and order of immune responses in the bovine corpus luteum following exposure of luteal cells to the luteolytic hormone, prostaglandin F2alpha (PGF), both in cows and in cultures of bovine luteal cells. Expression of the interleukin 8 gene was increased within 1 hour after cows were treated with a dose of PGF that causes regression of the corpus luteum. Interleukin 8 stimulated immune cell recruitment into the corpus luteum but did not inhibit progesterone production by luteal cells. These data indicate that interleukin 8 and proper immune signaling are involved in destruction of the luteal tissue, but are not responsible for the decrease in progesterone secretion during PGF-induced regression of the bovine corpus luteum.

Technical Abstract: Recent studies suggest that chemokines may mediate the luteolytic action of PGF2a (PGF). Our objective was to identify chemokines induced by PGF in vivo and to determine the effects of IL8 on specific luteal cell types in vitro. Midcycle cows were injected with saline or PGF, ovaries were removed after 0.5 - 4 h and chemokine expression was analyzed by qPCR. In vitro expression of IL8 was analyzed after PGF administration and with cell signaling inhibitors to determine the mechanism of PGF-induced chemokine expression. Purified neutrophils were analyzed for migration and activation in response to IL8 and PGF. Purified luteal cell types (steroidogenic, endothelial and fibroblast cells) were used to identify which cells respond to chemokines. Neutrophils and peripheral blood mononuclear cells (PBMCs) were co-cultured with steroidogenic cells to determine their effect on progesterone production. IL8, CXCL2, CCL2, and CCL8 transcripts were rapidly increased following PGF treatment in vivo. The stimulatory action of PGF on IL8 mRNA expression in vitro was prevented by inhibition of p38 and JNK signaling. IL8, but not PGF, TNF, or TGFB1, stimulated neutrophil migration. IL8 had no apparent action in purified luteal steroidogenic, endothelial, or fibroblast cells, but IL8 stimulated ERK phosphorylation in neutrophils. In co-culture experiments neither IL8 nor activated neutrophils altered basal or LH-stimulated luteal cell progesterone synthesis. In contrast, activated PBMCs inhibited LH-stimulated progesterone synthesis from cultured luteal cells. These data implicate a complex cascade of events during luteolysis involving chemokine signaling, neutrophil recruitment, and immune cell action within the corpus luteum.