Endogenous interleukin 18 regulates testicular germ cell apoptosis during endotoxemia.
Orchitis (testicular swelling) often occurs during systemic inflammatory conditions, such as sepsis. Interleukin 18 (IL18) is a proinflammatory cytokine and is an apoptotic mediator during endotoxemia, but the role of IL18 in response to inflammation in the testes was unclear. WT and IL18 knockout (KO) mice were injected lipopolysaccharide (LPS) to induce endotoxemia and examined 12 and 48  h after LPS administration to model the acute and recovery phases of endotoxemia. Caspase activation was assessed using immunohistochemistry. Protein and mRNA expression were examined by western blot and quantitative real-time RT-PCR respectively. During the acute phase of endotoxemia, apoptosis (as indicated by caspase-3 cleavage) was increased in WT mice but not in IL18 KO mice. The death receptor-mediated and mitochondrial-mediated apoptotic pathways were both activated in the WT mice but not in the KO mice. During the recovery phase of endotoxemia, apoptosis was observed in the IL18 KO mice but not in the WT mice. Activation of the death-receptor mediated apoptotic pathway could be seen in the IL18 KO mice but not the WT mice. These results suggested that endogenous IL18 induces germ cell apoptosis via death receptor mediated- and mitochondrial-mediated pathways during the acute phase of endotoxemia and suppresses germ cell apoptosis via death-receptor mediated pathways during recovery from endotoxemia. Taken together, IL18 could be a new therapeutic target to prevent orchitis during endotoxemia.
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Taketo
T
Inoue
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Michiko
M
Aoyama-Ishikawa
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Shingo
S
Kamoshida
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Satoshi
S
Nishino
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Maki
M
Sasano
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Nobuki
N
Oka
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Hayato
H
Yamashita
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Motoki
M
Kai
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Atsunori
A
Nakao
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan.
Joji
J
Kotani
Department of BiophysicsKobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142 Hyogo, JapanOno Ladies Clinic538-3, Nishihonmachi, Ono, 675-1375 Hyogo, JapanDepartment of EmergencyDisaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, 663-8501 Hyogo, Japan musa@kobe-u.ac.jp.
Makoto
M
Usami
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D019446:Endotoxemia / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005854:Germ Cells / Q000187:drug effects*; D020382:Interleukin-18 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009920:Orchitis / Q000139:chemically induced / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053218:Receptors, Death Domain / Q000187:drug effects / Q000235:genetics; D012772:Shock, Septic / Q000139:chemically induced / Q000523:psychology; D013737:Testis / Q000166:cytology / Q000187:drug effects*
D020382:Interleukin-18; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D053218:Receptors, Death Domain; D020169:Caspases