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.
Highlights
Renal inflammation, glomerular mesangial cell (GMC) proliferation, and matrix overproduction are key features of human mesangial proliferative glomerulonephritis (MsPGN), such as IgA nephropathy [1,2,3]
To make sure that the increase of Krüppel-like factor 4 (KLF4) and IL-6 is due to assembly of sublytic C5b-9 complex, GMCs were treated with sublytic C5b-9, Thy-1 Ab, Thy-1 Ab + Heat-inactivated serum (HIS), Thy-1Ab + C6-deficient serum (C6DS), and MEM for 3 h
We have found that IL-6 is obviously upregulated both in the renal tissues of Thy-1 nephritis (Thy-1N) rats and in GMCs exposed to sublytic C5b-9 [8], but the molecular mechanisms regulating its expression have not been completely understood
Summary
Glomerular mesangial cell (GMC) proliferation, and matrix overproduction are key features of human mesangial proliferative glomerulonephritis (MsPGN), such as IgA nephropathy [1,2,3]. Thy-1 nephritis (Thy-1N) as a popular experimental model for MsPGN is induced in the rat by injection of antibody to Thy-1, triggering activation of the complement system and subsequent formation of C5b-9 on the surface of GMC membranes [4,5,6]. In the early stage of Thy-1N, a number of proinflammatory cytokines are produced by GMCs in response to sublytic C5b-9 stimulus [8,9,10]. Of these proinflammatory cytokines, interleukin-6 (IL-6) overexpression has been detected in kidney biopsies and in the urine of patients with IgA nephropathy [11]. The exact role of IL-6 in MsPGN remains to be determined, exploring regulatory mechanisms of IL-6 expression in sublytic C5b-9attacked rat GMCs is beneficial to understand the role of IL-6 in human MsPGN
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