Endothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NFκB

Abstract

Sepsis is a severe systemic inflammatory response to infection. Endothelial activation and dysfunction play a critical role in the pathophysiology of sepsis and represent an important therapeutic target to reduce sepsis mortality. Interferon regulatory factor 1 (IRF-1) was recently identified as a downstream target of TNF-α-mediated signal transduction in endothelial cells. The aim of this study was to explore the importance of IRF-1 as a regulator of lipopolysaccharide (LPS)-induced endothelial proinflammatory activation. We found that renal IRF-1 was upregulated by LPS in vivo as well as in LPS-stimulated endothelial cells in vitro. Furthermore, we identified intracellular retinoic acid inducible gene-I (RIG-I) as a regulator of LPS-mediated IRF-1 induction. IRF-1 depletion specifically resulted in diminished induction of VCAM-1 in response to LPS, but not of E-selectin or ICAM-1, which was independent of NFκB signaling. When both IRF-1 and the RIG-I adapter protein mitochondrial antiviral signaling (MAVS) were absent, VCAM-1 induction was not additionally inhibited, suggesting that MAVS and IRF-1 reside in the same signaling pathway. Surprisingly, E-selectin and IL-6 induction were no longer inhibited by MAVS knockdown when IRF-1 was also absent, revealing a redundant endothelial activation pathway. In summary, we report an IRF-1-mediated proinflammatory signaling pathway that specifically regulates LPS-mediated VCAM-1 expression, independent of NFκB.

IRF‐1 promotes renal fibrosis by downregulation of Klotho

“…It has been reported that TNF‐α can induce Klotho reduction in animal models of kidney injury or systemic inflammation . Moreover, IRF‐1 is identified as a downstream target of TNF‐α‐mediated signal transduction in sepsis . However, In present study, our results indicated that the enhanced expression of IRF‐1 after UUO may be induced by TNF‐α, followed by Klotho reduction in tubular epithelial cells and renal fibrosis.…”

“…58,59 Moreover, IRF-1 is identified as a downstream target of TNF-α-mediated signal transduction in sepsis. 40 However, In present study, our results indicated that the enhanced expression of IRF-1 after UUO may be induced by TNF-α, followed by Klotho reduction in tubular epithelial cells and renal fibrosis. To some extent, the results also suggested that the inhibition of TNF-α on the expression of Klotho may be achieved by upregulating IRF-1.…”

“…Interferon regulatory factor 1 is a key regulator of transcription factors in the induction of inflammatory injury and immune responses. 13,40 Interestingly, IRF-1 can function as either an activator or a repressor of target genes, depending on the specific transcriptional machinery. 42,43 Previously, it was reported that IRF-1 was relevant to fibrotic disease.…”

“…As known, TNF-α could not only induce IRF-1 expression, but also promote renal fibrosis. 40,41 As shown in Figure 5A, in HK-2 cells, TNF-α enhanced IRF-1 expression and there existed dose-dependent effect. Moreover, following TNF-α treatment in HK-2 cells, we observed a markedly decrease in C/EBP-β and Klotho expression and a dramatic increase in the expression of ɑ-SMA and fibronectin (Figure 5B,C).…”

Bystander Cells Taking Action

“…The key importance of and continued research interest in Toll-like receptors are reflected in the articles by Yan et al [16] and Koymans et al [17]. Despite the fact that the discovery of their importance in innate immunity was more than 2 decades ago, they continue to surprise with regard to their broad effects on regulating both innate and adaptive immunity [18,19,20,21].…”