Characterization, localization and possible anti-inflammatory function of rat histone H4 mRNA variants

Two histone H4 mRNA variants, H4-v.1 and histogranin mRNAs, were detected in the rat genome and measured in various tissues and isolated alveolar macrophages. Medium to high levels of both mRNAs were present in the liver, adrenal glands, thymus, bone marrow and alveolar macrophages. H4-v.1 cDNA contained an open reading frame that coded for unmodified whole histone H4, whereas histogranin cDNA lacked the first ATG codon and contained an open reading frame that coded for modified (Thr89) H4-(84-102). The two genes displayed a sequence homologous (> 80%) to the open reading frame of core H4 somatic (H4s) and H4 germinal (H4g) and their variant nature was supported by the absence of histone consensus palindromic and purine-rich sequences in the proximal 3'UTR, and the presence of a polyadenylation signal in the distal 3'UTR and of specific upstream transcription factor-binding sites. H4-v.1 and histogranin transcripts, but not H4s transcript, were selectively induced by lipopolysaccharide and/or interferon gamma in alveolar macrophages. In vitro transcription/translation experiments with H4-v.1 and histogranin cDNA pCMV constructs produced peptides with the molecular mass (2 kDa) of the alternative histone H4 translation product which, like synthetic H4-(86-100) and [Thr89]H4-(86-100) or rat histogranin, inhibited lipopolysaccharide-induced prostaglandin E-2 release from rat alveolar macrophages. The synthetic peptides also inhibited the secretion of the CXC chemokine interleukin-8 (GRO/CINC-1) in response to lipopolysaccharide. The presence of H4-v.1 and histogranin mRNAs in tissues wherein immune reactions take place and the inhibitory effects of their translation products on prostaglandin E-2 and interkeukin-8 secretion by activated alveolar macrophages suggest an anti-inflammatory function.