Modulation of IL-6 Expression by KLF4-Mediated Transactivation and PCAF-Mediated Acetylation in Sublytic C5b-9-Induced Rat Glomerular Mesangial Cells

Abstract

Interleukin-6 (IL-6) overproduction has been considered to contribute to inflammatory damage of glomerular mesangial cells (GMCs) in human mesangial proliferative glomerulonephritis (MsPGN) and its rat model called Thy-1 nephritis (Thy-1N). However, the regulatory mechanisms of IL-6 expression in GMCs upon sublytic C5b-9 timulation remain poorly understood. We found that Krüppel-like factor 4 (KLF4) bound to the IL-6 promoter (−618 to −126 nt) and activated IL-6 gene transcription. Furthermore, lysine residue 224 of KLF4 was acetylated by p300/CBP-associated factor (PCAF), which was important for KLF4-mediated transactivation. Moreover, lysine residue 5 on histone H2B and lysine residue 9 on histone H3 at the IL-6 promoter were also acetylated by PCAF, which resulted in an increase in IL-6 transcription. Besides, NF-κB activation promoted IL-6 expression by elevating the expression of PCAF. Overall, these findings suggest that sublytic C5b-9-induced the expression of IL-6 involves KLF4-mediated transactivation, PCAF-mediated acetylation of KLF4 and histones, and NF-κB activation in GMCs.

Epigenetic Regulation of Inflammatory Signaling and Inflammation-Induced Cancer

“…Histone H3 lysine 9 acetylation (H3K9ac) has been highlighted as their signature target, as loss of GCN5 and PCAF in cells specifically causes H3K9ac reduction ( Jin et al, 2011 ). Importantly, genetic deletion or pharmacological inhibition of PCAF results in a significant reduction of H3K5ac and H3K9ac levels at the promoter region of the cytokine gene IL-6, leading to its transcriptional downregulation ( Xia et al, 2021 ). Upon treatment with the proinflammatory stimulus LPS, PCAF displays a positive correlation with H3K18ac expression, which activates the transcription levels of inflammatory genes ( Huang et al, 2015 ).…”

“…Aside from histone acetylation, GCN5/PCAF can also exert non-histone acetylation functions, which play an integral role in regulating inflammation as well. For example, PCAF acetylates the KLF4 TF to facilitate its transactivation effect on IL-6 ( Xia et al, 2021 ).…”

Differential expression profile of urinary exosomal microRNAs in patients with mesangial proliferative glomerulonephritis

“…Sublytic C5b-9 induces apoptosis via MEKK2-p38 MAPK-IRF-1-TRADD-Caspase 8 in rat Thy-1 nephritis in GMCs [ 34 ]. The inflammatory response is thought to be an important factor in the MsPGN development [ 35 , 36 ]. C5α is a potent pro-inflammatory mediator that correlates with the severity of various renal diseases and induces the synthesis of IL-6 and TNF-α in rat GMCs through MAPK signaling pathway activation [ 37 ].…”

KAT2paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells

“…We therefore aimed to understand whether KAT2A and KAT2B regulate the interferon response through means beyond transcriptional changes associated with H3K9ac loss. KAT2A and KAT2B are reported to directly acetylate non-histone proteins in controlling various biological functions in the cell 32,57,[67][68][69][70][71][72] . To investigate what proteins may be under Kat2dependent acetylation, we utilized acetylomic mass spectrometry of intestinal epithelial lysates from control versus Kat2 DKO mice (Fig.…”

“…Both KAT2A and KAT2B are reported to redundantly catalyze acetylation of lysine residues on histone H3 tails, particularly lysines 9 and 14 (H3K9ac and H3K14ac, respectively). Additionally, these acetyltransferases also catalyze other acetyl and non-acetyl marks [19][20][21][22][23][24][25][26][27][28][29][30][31][32] .…”