Reversible Histone Acetylation/deacetylation Modification By P300/HDACs Is Involved In The Regulation Of IL-12/IL-18 Transcriptional Activity

Interleukin-12 (IL-12) is a heterodimeric cytokine produced by macrophages in response to intracellular pathogens, and provides an obligatory signal for the differentiation of T-helper-1 cells. Interleukin-18 (IL-18) is a pleiotropic cytokine involved in the development of T helper type 1 (Thl) cells, and it plays important roles in regulation of both the innate and acquired immune responses.It is now clear that the reversible acetylation/deacetylation modification of core histone tails is involved in the modulation of chromatin structure and function that leads to the activation/suppression of gene expression. This reversible modification is accomplished by two categories of enzymes, i.e., histone acetyltransferases (HATs) and histone deacetylases (HDACs). p300 is an important HAT and has implicated in the regulation of gene expression, including many cytokine genes. HDACs play the opposite role in the gene regulation. HDACs remove acetyl moieties from specific lysine residues of core histones to keep the levels of histone acetylation at a steady state.Although it has long been known that acetylation modification plays an important role in gene transcription, whether it is involved in the regulation of IL-12/IL-18 expression had not been investigated up to this study. The aim of this study was to elucidate whether the reversible histone acetylation/deacetylation modification mediated by p300/HDACs participates in the regulation of IL-12/IL-18 transcription expression and whether the HAT activity of p300 is necessary for its function.In this study, we analyzed the roles of p300/HDACs in the regulation of IL-12/IL-18 by using RT-PCR, ChIP and a series of co-transfection studies. The results demonstrate that p300 stimulated the activation of IL-12 p40/IL-18 pi promoter and the HAT activity of p300 was essential to its function. In addition, p300 was shown to be able to work synergistically with the transcription factors on activation of IL-12 p40/IL-18 p1 promoter and this effect could be impaired by HDACs.Furtherajiore, p300 promoted the endogenous IL-12 p40/IL-18 mRNA synthesis and enhanced the acetylation of the histone H3 at IL-12 p40 promotejr. Results presented in this paper indicate that the reversible histone cetylation/deacetylation modification plays an important role in the trans|criptional regulation of IL-12 p40/IL-18. All these original results will be (helpful in establishing theoretical bases for the cure of diseases associated with IL-12/IL-18.