TNF‐α inhibits aquaporin 5 expression in human salivary gland acinar cells via suppression of histone H4 acetylation

Abstract

Sjögren's syndrome is a systemic autoimmune disease characterized by reductions in salivary and lacrimal secretions. The mechanisms underlying these reductions remain unclear. We have previously shown that TNF-α plays an important role in the destruction of acinar structures. Here we examined TNF-α's function in the expression of aquaporin (AQP) 5 in human salivary gland acinar cells. Immortalized human salivary gland acinar (NS-SV-AC) cells were treated with TNF-α, and then the expression levels of AQP5 mRNA and protein were analysed. In addition, the mechanisms underlying the reduction of AQP5 expression by TNF-α treatment were investigated. TNF-α-treatment of NS-SV-AC cells significantly suppressed the expression levels of AQP5 mRNA and protein, and reduced the net fluid secretion rate. We examined the expression and activation levels of DNA methyltransferases (Dnmts) in NS-SV-AC cells treated with TNF-α. However, no significant changes were observed in the expression or activation levels of Dnmt1, Dnmt3a or Dnmt3b. Although we also investigated the role of NF-κB activity in the TNF-α-induced suppression of AQP5 expression in NS-SV-AC cells, we detected similar TNF-α suppression of AQP5 expression in non-transfected cells and in a super-repressor form of IκBα cDNA-transfected cell clones. However, interestingly, chromatin immunoprecipitation analysis demonstrated a remarkable decrease in levels of acetylated histone H4 associated with the AQP5 gene promoter after treatment with TNF-α in NS-SV-AC cells. Therefore, our results may indicate that TNF-α inhibition of AQP5 expression in human salivary gland acinar cells is due to the epigenetic mechanism by suppression of acetylation of histone H4.

Aqp5 Is a New Transcriptional Target of Dot1a and a Regulator of Aqp2

“…TNFα-mediated repression involves suppression of histone H4 acetylation [40]. Lipopolysaccharide enhances NF-κB, but not AP-1 binding at the Aqp5 promoter [41].…”

“…TNFα and lipopolysaccharide inhibit Aqp5 expression in salivary and parotid gland cells, respectively [40], [41]. TNFα-mediated repression involves suppression of histone H4 acetylation [40].…”

Pathogenic role of endogenous TNF-α in the development of Sjögren's-like sialadenitis and secretory dysfunction in non-obese diabetic mice

“…In addition, TNF-α treatment can augment expression of Ro/SSA and La/SSB in human keratinocytes, two autoantigens closely associated with SS disease 27 . Moreover, in human salivary gland acinar cells, TNF-α treatment down-regulates the expression suppression of aquaporin 5 (AQP5), a water channel protein required for salivary secretion 28–31 . Taken together, these lines of evidence suggest that TNF-α may be a pathogenic factor in the SS and its inhibition may impede the development or attenuate the severity of this disease.…”

Epigenetics of Autoimmune Diseases

“…The methylation profi le of the gene coding for the interferon regulatory factor 5 ( IRF5 ) was investigated in CD4+ T cells, B lymphocytes, and monocytes from patients with SjS, but the observed methylation levels were similar to those observed in cells from controls (Gestermann et al 2012 ). Abnormal distribution of aquaporin 5 (AQP5) in salivary gland acini is likely to contribute to the defi ciency of fl uid secretion in SjS, and the tumor necrosis factor alpha plays an important role in the destruction of acinar structures in exocrine glands, Sievers et al ( 2012 ) and inhibits AQP5 gene expression in human salivary gland acinar cells by suppression of acetylation of histone H4 in the promoter region (Yamamura et al 2012 ). Also some miRNAs were found to be deregulated in SjS salivary glands (miR-547 and miR-768-3p) and/or in peripheral mononuclear cells (miR-146a and miR-146b) (Alevizos et al 2011 ;Pauley et al 2011 ;Zilahi et al 2012 ).…”