title: Hormonal regulation of the cytokine microenvironment in the mammary gland.
abstract: The mammary gland is a unique organ that undergoes hormone-driven developmental changes over the course of the ovarian cycle during adult life. Macrophages play a role in regulating cellular turnover in the mammary gland and may affect cancer susceptibility. However, the immune microenvironment that regulates macrophage function has not been described. Hormonal regulation of the cytokine microenvironment across the ovarian cycle was explored using microbead multiplex assay for 15 cytokines in mammary glands from C57Bl/6 mice at different stages of the oestrous cycle, and in ovariectomised mice administered oestradiol and progesterone. The cytokines that were found to fluctuate over the course of the oestrous cycle were colony-stimulating factor (CSF)1, CSF2, interferon gamma (IFNG) and tumour necrosis factor alpha (TNFA), all of which were significantly elevated at oestrus compared with other phases. The concentration of serum progesterone during the oestrus phase negatively correlated with the abundance of cytokines CSF3, IL12p40, IFNG and leukaemia inhibitory factor (LIF). In ovariectomised mice, exogenous oestradiol administration increased mammary gland CSF1, CSF2, IFNG and LIF, compared with ovariectomised control mice. Progesterone administration together with oestradiol resulted in reduced CSF1, CSF3 and IFNG compared with oestradiol administration alone. This study suggests that the cytokine microenvironment in the mammary gland at the oestrus phase of the ovarian cycle is relatively pro-inflammatory compared with other stages of the cycle, and that the oestradiol-induced cytokine microenvironment is significantly attenuated by progesterone. A continuously fluctuating cytokine microenvironment in the mammary gland presumably regulates the phenotypes of resident leukocytes and may affect mammary gland cancer susceptibility.
authors.affiliation: Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Australia; Research Centre for Reproductive Health, The Robinson Institute, University of Adelaide, Australia.
authors.forename: Pallave
authors.initials: P
authors.lastname: Dasari
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Australia; Research Centre for Reproductive Health, The Robinson Institute, University of Adelaide, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sharkey
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Australia; Research Centre for Reproductive Health, The Robinson Institute, University of Adelaide, Australia.
authors.forename: Effarina
authors.initials: E
authors.lastname: Noordin
authors.affiliation: Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Australia; Research Centre for Reproductive Health, The Robinson Institute, University of Adelaide, Australia.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Glynn
authors.affiliation: Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Australia; Research Centre for Reproductive Health, The Robinson Institute, University of Adelaide, Australia.
authors.forename: Leigh J
authors.initials: LJ
authors.lastname: Hodson
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Australia; Research Centre for Reproductive Health, The Robinson Institute, University of Adelaide, Australia.
authors.forename: Peck Y
authors.initials: PY
authors.lastname: Chin
authors.affiliation: Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Australia; Research Centre for Reproductive Health, The Robinson Institute, University of Adelaide, Australia.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Robertson
authors.affiliation: Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Australia; Research Centre for Reproductive Health, The Robinson Institute, University of Adelaide, Australia. Electronic address: wendy.ingman@adelaide.edu.au.
authors.forename: Wendy V
authors.initials: WV
authors.lastname: Ingman
mesh_terms: D000818:Animals; D060833:Cellular Microenvironment / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D008321:Mammary Glands, Animal / Q000378:metabolism*; D008597:Menstrual Cycle / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D011374:Progesterone / Q000097:blood / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D004958:Estradiol; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Cytokines; Inflammation; Mammary gland; Oestrogen; Progesterone