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Interleukin-18 levels and mouse Leydig cell apoptosis during lipopolysaccharide-induced acute inflammatory conditions.
J Reprod Immunol. 2020 Jun 20; 141:103167.JR

Abstract

Interleukin (IL)-18 is an inflammasome-mediated cytokine produced by germ cells, Leydig cells, and resident macrophages that is indispensable in the maintenance of homeostasis in the testis. We previously demonstrated that endogenous IL-18 induces testicular germ cell apoptosis during acute inflammation when plasma IL-18 levels are very high. However, the impact of acute inflammation and IL-18 on Leydig cells remained unclear. TM3 cells, a mouse Leydig cell line, and RAW264.7 cells, a mouse macrophage cell line, were stimulated with lipopolysaccharide (LPS) or recombinant IL-18 (rIL-18). We assessed the expression of inflammatory cytokines, caspase cleavage, and markers of apoptotic pathways. In Leydig cells, caspase 3 cleavage was increased and death-receptor-mediated apoptotic pathways were activated after LPS stimulation. However, LPS stimulation did not increase IL-18 expression in the Leydig cell line. When high-dose rIL-18 was administered to the Leydig cell line to mimic levels seem after inflammation, rIL-18 upregulated Tnf-α mRNA, Fadd mRNA, and Fas protein, promoted cleavage of caspase-8 and caspase-3, and induced apoptosis. Low-dose rIL-18 did not stimulate apoptosis. To determine if the high level of IL-18 seen in the testes after inflammation was derived from immune cells, we examined IL-18 protein expression in a macrophage cell line, RAW264.7. In contrast to the TM3 cells, IL-18 was significantly increased in RAW264.7 cells after LPS stimulation. These results suggest that high-dose IL-18 derived from macrophages is harmful to Leydig cells. Reducing the overexpression of IL-18 could be a new therapeutic approach to prevent Leydig cell apoptosis as a result of acute inflammation.

Authors+Show Affiliations

Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan. Electronic address: taketoein@yahoo.co.jp.Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.Department of Rehabilitation, Faculty of Health Science, Kansai University of Welfare Science, 3-11-1, Asahigaoka, Kashiwara, 582-0026, Osaka, Japan.Department of Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142, Hyogo, Japan.Department of Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142, Hyogo, Japan.Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.Department of Clinical Nutrition and Dietetics, Konan Women's University, 6-2-23, Morikita-machi, Higashinada-ku, Kobe, 658-0001, Hyogo, Japan.Division of Disaster and Emergency Medicine, Department of Surgery Related, Kobe University Graduate School of Medicine, 7-5-2, Kusunocho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32629316

Citation

Inoue, Taketo, et al. "Interleukin-18 Levels and Mouse Leydig Cell Apoptosis During Lipopolysaccharide-induced Acute Inflammatory Conditions." Journal of Reproductive Immunology, vol. 141, 2020, p. 103167.
Inoue T, Aoyama-Ishikawa M, Uemura M, et al. Interleukin-18 levels and mouse Leydig cell apoptosis during lipopolysaccharide-induced acute inflammatory conditions. J Reprod Immunol. 2020;141:103167.
Inoue, T., Aoyama-Ishikawa, M., Uemura, M., Yamashita, H., Koga, Y., Terashima, M., Usami, M., Kotani, J., & Hirata, J. (2020). Interleukin-18 levels and mouse Leydig cell apoptosis during lipopolysaccharide-induced acute inflammatory conditions. Journal of Reproductive Immunology, 141, 103167. https://doi.org/10.1016/j.jri.2020.103167
Inoue T, et al. Interleukin-18 Levels and Mouse Leydig Cell Apoptosis During Lipopolysaccharide-induced Acute Inflammatory Conditions. J Reprod Immunol. 2020 Jun 20;141:103167. PubMed PMID: 32629316.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interleukin-18 levels and mouse Leydig cell apoptosis during lipopolysaccharide-induced acute inflammatory conditions. AU - Inoue,Taketo, AU - Aoyama-Ishikawa,Michiko, AU - Uemura,Mikiko, AU - Yamashita,Hayato, AU - Koga,Yuka, AU - Terashima,Mariko, AU - Usami,Makoto, AU - Kotani,Joji, AU - Hirata,Junichi, Y1 - 2020/06/20/ PY - 2020/02/29/received PY - 2020/05/20/revised PY - 2020/06/10/accepted PY - 2020/7/7/pubmed PY - 2020/7/7/medline PY - 2020/7/7/entrez SP - 103167 EP - 103167 JF - Journal of reproductive immunology JO - J. Reprod. Immunol. VL - 141 N2 - Interleukin (IL)-18 is an inflammasome-mediated cytokine produced by germ cells, Leydig cells, and resident macrophages that is indispensable in the maintenance of homeostasis in the testis. We previously demonstrated that endogenous IL-18 induces testicular germ cell apoptosis during acute inflammation when plasma IL-18 levels are very high. However, the impact of acute inflammation and IL-18 on Leydig cells remained unclear. TM3 cells, a mouse Leydig cell line, and RAW264.7 cells, a mouse macrophage cell line, were stimulated with lipopolysaccharide (LPS) or recombinant IL-18 (rIL-18). We assessed the expression of inflammatory cytokines, caspase cleavage, and markers of apoptotic pathways. In Leydig cells, caspase 3 cleavage was increased and death-receptor-mediated apoptotic pathways were activated after LPS stimulation. However, LPS stimulation did not increase IL-18 expression in the Leydig cell line. When high-dose rIL-18 was administered to the Leydig cell line to mimic levels seem after inflammation, rIL-18 upregulated Tnf-α mRNA, Fadd mRNA, and Fas protein, promoted cleavage of caspase-8 and caspase-3, and induced apoptosis. Low-dose rIL-18 did not stimulate apoptosis. To determine if the high level of IL-18 seen in the testes after inflammation was derived from immune cells, we examined IL-18 protein expression in a macrophage cell line, RAW264.7. In contrast to the TM3 cells, IL-18 was significantly increased in RAW264.7 cells after LPS stimulation. These results suggest that high-dose IL-18 derived from macrophages is harmful to Leydig cells. Reducing the overexpression of IL-18 could be a new therapeutic approach to prevent Leydig cell apoptosis as a result of acute inflammation. SN - 1872-7603 UR - https://www.unboundmedicine.com/medline/citation/32629316/Interleukin-18_levels_and_mouse_Leydig_cell_apoptosis_during_lipopolysaccharide-induced_acute_inflammatory_conditions L2 - https://linkinghub.elsevier.com/retrieve/pii/S0165-0378(20)30088-7 DB - PRIME DP - Unbound Medicine ER -
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