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CXCL10/CXCR3 signaling mediates inhibitory action by interferon-gamma on CRF-stimulated adrenocorticotropic hormone (ACTH) release

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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.

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Authors and Affiliations

  1. Laboratory of Anatomy and Cell Biology, Department of Health Sciences, Kyorin University, 476 Miyashita-cho, Hachioji, Tokyo, 192-8508, Japan

    Kotaro Horiguchi, Kozue Tateno, Rumi Hasegawa, Shu Takigami & Shunji Ohsako

  2. Institute of Reproduction and Endocrinology, Meiji University, Kanagawa, Japan

    Kotaro Horiguchi, Masashi Higuchi, Takako Kato & Yukio Kato

  3. Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University School of Medicine, Tochigi, Japan

    Ken Fujiwara, Takehiro Tsukada & Takashi Yashiro

  4. Division of Life Science, Graduate School of Agriculture, Meiji University, Kanagawa, Japan

    Saishu Yoshida & Yukio Kato

  5. Department of Life Science, School of Agriculture, Meiji University, Kanagawa, Japan

    Yukio Kato

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  1. Kotaro Horiguchi
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  2. Ken Fujiwara
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  3. Takehiro Tsukada
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  4. Saishu Yoshida
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  5. Masashi Higuchi
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  6. Kozue Tateno
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  10. Takashi Yashiro
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Corresponding author

Correspondence to Kotaro Horiguchi.

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Conflict of interest

The authors have no conflict of interest that might prejudice the impartiality of this research.

Funding

This work was supported by a Grant-in-Aid for Young Scientists (B) (no. 25860148 to K.H.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by the Kyorin University Individual Investigator Award from the Faculty of Health Sciences, Kyorin University. It was also partially supported by JSPS KAKENHI Grants (nos. 21380184 to Y.K. and 24580435 to T.K.), by a MEXT-supported Program for the Strategic Research Foundation at Private Universities, 2014–2018 and by the Meiji University International Institute for BioResource Research (MUIIR).

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Fig. S1

The expression of Ifng, Ifngr1 and Ifngr2 in S100β-positive cells. Their mRNA levels, as determined by real-time PCR, were normalized with an internal control b-actin (mean ± SEM, n = 3). (a) Ifng, Ifngr1 and Ifngr2 mRNA levels in the rat anterior pituitary gland (anterior pituitary gland) of adult. (b) Ifngr1 and Ifngr2 mRNA levels in S100β-positive cells (S100β-positive cells). N.D., Not detected. (GIF 17 kb)

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Table S1

Primers for real-time RT-PCR. (GIF 75 kb)

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Horiguchi, K., Fujiwara, K., Tsukada, T. et al. CXCL10/CXCR3 signaling mediates inhibitory action by interferon-gamma on CRF-stimulated adrenocorticotropic hormone (ACTH) release. Cell Tissue Res 364, 395–404 (2016). https://doi.org/10.1007/s00441-015-2317-2

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  • DOI: https://doi.org/10.1007/s00441-015-2317-2

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