title: Regulation of the estrous cycle by neutrophils via opioid peptides.
abstract: We found previously that neutrophil-depleted mice exhibited significant blockading of both the regular estrous cycle and cyclic changes of steroid hormone levels. In this study, we aimed at elucidation of the underlying mechanism. To examine the possibility that an increase in bacteria in the vaginal vault of neutrophil-depleted mice causes blockading of the estrous cycle, we treated neutrophil-depleted mice with antibiotics but failed to restore the estrous cycle. We then examined another possibility that neutrophils regulate the estrous cycle via opioid peptides, because opioid peptides regulate steroidogenesis in theca and granulosa cells in the ovaries, and because neutrophils contain opioid peptides. In support of this possibility, naloxone, an opioid antagonist, blocked the estrous cycle and a μ opioid receptor agonist restored the estrous cycle in neutrophil-depleted mice. Pro-opiomelanocortin was immunohistochemically detected in peripheral blood neutrophils but not in ones that had infiltrated into the ovaries. i.v. injection of anti-MIP-2 polyclonal Ab caused blockading of the estrous cycle, whereas MIP-2 was detected in the ovaries, suggesting a role of MIP-2 in the regulation of the estrous cycle. Moreover, i.v. injection of MIP-2 decreased the pro-opiomelanocortin signal in peripheral blood neutrophils and caused blockading of the estrous cycle. Together, these results suggest that neutrophils maintain the estrous cycle via opioid peptides.
authors.affiliation: Division of Molecular Medicine, Department of Biomolecular Science, Faculty of Science, Toho University, Funabashi, Chiba 274-8510, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Sasaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamaki
authors.forename: Kisaburo
authors.initials: K
authors.lastname: Nagata
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000502:physiology; D030762:Estrous Cycle / Q000187:drug effects / Q000276:immunology*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D009270:Naloxone / Q000494:pharmacology; D009503:Neutropenia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018847:Opioid Peptides / Q000378:metabolism / Q000502:physiology*; D010053:Ovary / Q000276:immunology / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors; D001615:beta-Endorphin / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; D009270:Naloxone; D001615:beta-Endorphin