title: Up-regulation of histamine H4 receptors contributes to splenic apoptosis in septic mice: counteraction of the antiapoptotic action of nuclear factor-kappaB.
abstract: The histamine H(4) receptor is the most recently identified receptor and is considered to play a role in a variety of inflammatory diseases. Histamine levels in the plasma are known to be elevated in animal models of sepsis and in septic patients. The aim of this study was to test the hypothesis that the H(4) receptor may play a significant role in the pathophysiology of sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture in BALB/c mice. Although the H(4) receptor gene was undetectable in normal peripheral key organs, with the exception of the spleen, the expression levels of this gene were highly up-regulated in all those organs of septic mice. In vivo transfection of nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide, but not of its scrambled form, resulted in a great inhibition of sepsis-induced overexpression of the H(4) receptor gene. In septic mice, marked increases in caspase-3 activation and follicular lymphocyte apoptosis in spleens were strongly suppressed by systemic treatment with synthetic small interfering RNA (siRNA) targeted to the H(4) receptor. This was associated with the up-regulation of a number of antiapoptotic proteins. These antiapoptotic effects of H(4) receptor siRNA treatment were all inhibited by further application of NF-kappaB decoy oligonucleotide. Our results suggest that superinduction of the histamine H(4) receptor gene in peripheral key organs, including the spleen, that is promoted by sepsis is transcriptionally controlled by NF-kappaB, whereas stimulation of this receptor is involved in the development of sepsis-induced splenic apoptosis through counteraction of the antiapoptotic action of NF-kappaB.
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsuda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Teramae
authors.forename: Motonori
authors.initials: M
authors.lastname: Futatsugi
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takano
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Kaoru
authors.initials: K
authors.lastname: Koike
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D004789:Enzyme Activation; D008214:Lymphocytes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D009841:Oligonucleotides / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000235:genetics; D011968:Receptors, Histamine / Q000096:biosynthesis* / Q000235:genetics; D000074040:Receptors, Histamine H4; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology*; D013154:Spleen / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C498829:Hrh4 protein, mouse; D016328:NF-kappa B; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D053148:Caspase 3