Up-regulation of histamine H₄ receptors contributes to splenic apoptosis in septic mice: Counteraction of the antiapoptotic action of nuclear factor-κB

The histamine H₄ 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 H₄ 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 H₄ 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-κB (NF-κB) decoy oligodeoxynucleotide, but not of its scrambled form, resulted in a great inhibition of sepsis-induced overexpression of the H₄ 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 H₄ receptor. This was associated with the up-regulation of a number of antiapoptotic proteins. These antiapoptotic effects of H₄ receptor siRNA treatment were all inhibited by further application of NF-κB 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-κB, whereas stimulation of this receptor is involved in the development of sepsis-induced splenic apoptosis through counteraction of the antiapoptotic action of NF-κB.