Vasoactive Intestinal Peptide Enhances TNF-α-Induced IL-6 and IL-8 Synthesis in Human Proximal Renal Tubular Epithelial Cells by NF-κB-Dependent Mechanism

Abstract

Vasoactive intestinal polypeptide (VIP) is a 28-amino acid neuropeptide with vasodilator, bronchodilator, and anti-inflammatory effects. But little is known about its pro-inflammatory effects. We investigated the effect of VIP on the secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), two pro-inflammatory cytokines, in TNF-α-activated proximal renal tubular epithelial cell line (HK-2 cells). Cultured HK-2 cells were treated with TNF-α in the presence or absence of VIP with a dose range from 1 to 100 nM, followed by analysis of pro-inflammatory cytokines (IL-6 and IL-8) induction and their signal events including activation of the NF-κB pathway. We report here that tumor necrosis factor-α (TNF-α) increased IL-6 and IL-8 production, and that these effects were potentiated by VIP at 10 nM in HK-2 cells. However, VIP at 1 and 100 nM did not display this function. Consistent with these observations, we were able to show that VIP at 10 nM upregulated TNF-α-induced phosphorylation of IκB-α, leading to IκB-α degradation and the subsequent nuclear translocation of NF-κB. Furthermore, VIP-enhanced activation of NF-κB transcription activity was demonstrated using a NF-κB reporter construct upon transient transfection into HK-2 cells. These results strongly suggest that VIP synergistically enhances TNF-α-stimulated IL-6 and IL-8 synthesis via activating the NF-κB pathway in HK-2 cells.

Vasoactive Intestinal Peptide Deficiency Is Associated With Altered Gut Microbiota Communities in Male and Female C57BL/6 Mice

“…Using VIP KO mice, different studies showed an exacerbation or an amelioration of chemically induced colitis (Abad et al, 2015; Wu et al, 2015). The notion that VIP could have both pro- and anti-inflammatory actions is not unreasonable, as VIP differentially regulates IL-6 expression, which can act as a pro- and anti-inflammatory cytokine (Huang et al, 2012). Another explanation could be due to gut microbiota structure differences as recently suggested by Wu et al (2015).…”

Mefunidone Attenuates Tubulointerstitial Fibrosis in a Rat Model of Unilateral Ureteral Obstruction

“…Lipofectamine Transfection Reagents (Invitrogen) were used. After transfection as previously described [ 34 ], cells were cultured overnight and treated with 10ng/ml TNF-α in the presence or absence of Mefunidone (0.06, 0.12, and 0.18mM) or DXM (10 -6 M) as positive control. Luciferase activity was assessed using a luciferase assay substrate (Promega) according to manufacturer’s instructions.…”

Vasoactive intestinal peptide suppresses macrophage‐mediated inflammation by downregulating interleukin‐17A expression via PKA‐ and PKC‐dependent pathways

“…found that VIP increases TNF‐α‐induced production of IL‐6 and IL‐8 via activating the NF‐κB pathway in human proximal renal tubular epithelial cells (Huang et al . ). Moreover, it was also reported that VIP increases pro‐inflammatory osteotropic cytokines such as IL‐6 in an osteoblastic cell line (Persson & Lerner ).…”

“…However, VIP was also reported to enhance IL-6 secretion in unstimulated peritoneal macrophages as early as in the 1990s (Martinez et al 1998b). Ling et al found that VIP increases TNF-a-induced production of IL-6 and IL-8 via activating the NF-jB pathway in human proximal renal tubular epithelial cells (Huang et al 2012). Moreover, it was also reported that VIP increases pro-inflammatory osteotropic cytokines such as IL-6 in an osteoblastic cell line (Persson & Lerner 2005).…”