Up-Regulation of Histamine H-4 Receptors Contributes to Splenic Apoptosis in Septic Mice: Counteraction of the Antiapoptotic Action of Nuclear Factor-kappa B

Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 12/2009; 332(3):730-7. DOI: 10.1124/jpet.109.163543
Source: PubMed


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.

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    • "This process is a mechanism of tightly regulated disassembly of cells caused by activation of certain specialized proteases called caspases. A number of laboratories have demonstrated that sepsis induces extensive lymphocyte apoptosis, which can impairment of immunoresponses, thereby predisposing patients to septic death (Ayala & Chaudry, 1996; Wesche et al., 2005; Hotchkiss et al., 2005; Lang & Matute-Bello, 2009; Matsuda et al., 2010a). Parenchymal cells, including intestinal and lung epithelial cells, also have increased apoptotic cell death in animal models of sepsis (Coopersmith et al., 2002a, 2002b; Perl et al., 2007). "
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    • "HRH4 has been reported to influence apoptosis in animal models of sepsis through counteracting the anti-apoptotic action of NF-kappaB [30], while the cAMP-PKA pathway is involved in HRH4 activation-mediated cell death in peripheral blood mononuclear cells (PBMCs) [29]. In the current study, we showed that HRH4 activation could promote the 5-Fu-mediated cell apoptosis in colon cancer cells, which may provide new clues for histamine receptor-targeted therapies of CRCs. "
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    ABSTRACT: Introduction: Histamine H4 receptor (H4R) has been shown to be involved in various inflammatory conditions. Ligands acting on H4R show therapeutic potential in various diseases. For the first time, the positive proof-of-concept clinical trials of the H4 antagonist JNJ39758979 have demonstrated this potential in histamine-induced pruritus. Besides role of H4R in inflammatory conditions, preclinical results in cancer, neuropathic pain, vestibular disorders and type 2 diabetes show the diverse signaling network modulated by H4R. This suggests further potential for H4 ligands in such diseases. Areas covered: In this review, we have summarized patent applications and papers of the H4R field published between 2012 and 2014. Additionally, we have analyzed the quality of the already described H4 ligands in terms of their ligand efficiency, lipophilic ligand efficiency and lipophilicity-corrected ligand efficiency. Expert opinion: We demonstrate that the number of published patent applications reached a maximum in 2009 and showed some decrease in the last few years. On the other hand, the field is still very lively, reflected by the numerous publications on novel potential therapeutic applications. The favorable property profile of H4 ligands in development shows promise for the upcoming human clinical trials.
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