title: CXCL10/CXCR3 signaling mediates inhibitory action by interferon-gamma on CRF-stimulated adrenocorticotropic hormone (ACTH) release.
abstract: Secretion of hormones by the anterior pituitary gland can be stimulated or inhibited by paracrine factors that are produced during inflammatory reactions. The inflammation cytokine interferon-gamma (IFN-γ) is known to inhibit corticotropin-releasing factor (CRF)-stimulated adrenocorticotropin (ACTH) release but its signaling mechanism is not yet known. Using rat anterior pituitary, we previously demonstrated that the CXC chemokine ligand 10 (CXCL10), known as interferon-γ (IFN-γ) inducible protein 10 kDa, is expressed in dendritic cell-like S100β protein-positive (DC-like S100β-positive) cells and that its receptor CXCR3 is expressed in ACTH-producing cells. DC-like S100β-positive cells are a subpopulation of folliculo-stellate cells in the anterior pituitary. In the present study, we examine whether CXCL10/CXCR3 signaling between DC-like S100β-positive cells and ACTH-producing cells mediates inhibition of CRF-activated ACTH-release by IFN-γ, using a CXCR3 antagonist in the primary pituitary cell culture. We found that IFN-γ up-regulated Cxcl10 expression via JAK/STAT signaling and proopiomelanocortin (Pomc) expression, while we reconfirmed that IFN-γ inhibits CRF-stimulated ACTH-release. Next, we used a CXCR3 agonist in primary culture to analyze whether CXCL10 induces Pomc-expression and ACTH-release using a CXCR3 agonist in the primary culture. The CXCR3 agonist significantly stimulated Pomc-expression and inhibited CRF-induced ACTH-release, while ACTH-release in the absence of CRF did not change. Thus, the present study leads us to an assumption that CXCL10/CXCR3 signaling mediates inhibition of the CRF-stimulated ACTH-release by IFN-γ. Our findings bring us to an assumption that CXCL10 from DC-like S100β-positive cells acts as a local modulator of ACTH-release during inflammation.
authors.affiliation: Laboratory of Anatomy and Cell Biology, Department of Health Sciences, Kyorin University, 476 Miyashita-cho, Hachioji, Tokyo, 192-8508, Japan. kota@ks.kyorin-u.ac.jp.|Institute of Reproduction and Endocrinology, Meiji University, Kanagawa, Japan. kota@ks.kyorin-u.ac.jp.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Horiguchi
authors.affiliation: Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University School of Medicine, Tochigi, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University School of Medicine, Tochigi, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Tsukada
authors.affiliation: Division of Life Science, Graduate School of Agriculture, Meiji University, Kanagawa, Japan.
authors.forename: Saishu
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Institute of Reproduction and Endocrinology, Meiji University, Kanagawa, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Laboratory of Anatomy and Cell Biology, Department of Health Sciences, Kyorin University, 476 Miyashita-cho, Hachioji, Tokyo, 192-8508, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Tateno
authors.affiliation: Laboratory of Anatomy and Cell Biology, Department of Health Sciences, Kyorin University, 476 Miyashita-cho, Hachioji, Tokyo, 192-8508, Japan.
authors.forename: Rumi
authors.initials: R
authors.lastname: Hasegawa
authors.affiliation: Laboratory of Anatomy and Cell Biology, Department of Health Sciences, Kyorin University, 476 Miyashita-cho, Hachioji, Tokyo, 192-8508, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Takigami
authors.affiliation: Laboratory of Anatomy and Cell Biology, Department of Health Sciences, Kyorin University, 476 Miyashita-cho, Hachioji, Tokyo, 192-8508, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Ohsako
authors.affiliation: Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University School of Medicine, Tochigi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yashiro
authors.affiliation: Institute of Reproduction and Endocrinology, Meiji University, Kanagawa, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Kato
authors.affiliation: Institute of Reproduction and Endocrinology, Meiji University, Kanagawa, Japan.|Division of Life Science, Graduate School of Agriculture, Meiji University, Kanagawa, Japan.|Department of Life Science, School of Agriculture, Meiji University, Kanagawa, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D054367:Receptors, CXCR3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; C515189:Cxcr3 protein, rat; D054367:Receptors, CXCR3; D064568:S100 Calcium Binding Protein beta Subunit; D011333:Pro-Opiomelanocortin; D007371:Interferon-gamma; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone
keywords: ACTH; Anterior pituitary gland; CXCL10; CXCR3; Interferon-gamma; S100β protein-positive cells