TANK‐binding kinase 1 and Janus kinase 2 play important roles in the regulation of mitogen‐activated protein kinase phosphatase‐1 expression after toll‐like receptor 4 activation

Abstract

Inflammation is a response that protects the body from pathogens. Through several inflammatory signaling pathways mediated by various families of transcription factors, such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), interferon regulatory factors (IRFs), and signal transducers and activators of transcription (STATs), various inflammatory cytokines and chemokines are induced and inflammatory responses are boosted. Simultaneously, inhibitory systems are activated and provide negative feedback. A typical mechanism by which this process occurs is that inflammatory signaling molecules upregulate mitogen-activated protein kinase phosphatase-1 (MKP1) expression. Here, we investigated how kinases regulate MKP1 expression in lipopolysaccharide-triggered cascades. We found that p38 and c-Jun N-terminal kinase (JNK) inhibitors decreased MKP1 expression. Using specific inhibitors, gene knockouts, and gene knockdowns, we also found that tumor necrosis factor receptor-associated factor family member-associated nuclear factor κB activator (TANK)-binding kinase 1 (TBK1) and Janus kinase 2 (JAK2) are involved in the induction of MKP1 expression. By analyzing JAK2-induced activation of STATs, STAT3-specific inhibitors, promoter binding sites, and STAT3 cells, we found that STAT3 is directly linked to TBK1-mediated and JAK2-mediated induction of MKP1 expression. Our data suggest that MKP1 expression can be differentially regulated by p38, JNK, and the TBK1-JAK2-STAT3 pathway after activation of toll-like receptor 4 (TLR4). These data also imply crosstalk between the AP-1 pathway and the IRF3 and STAT3 pathways.

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

“…The sgRNA was cloned within a lentiCRISPRv2 vector (plasmid ID #52961; Addgene, Cambridge, MA, USA). Transfection and puromycin (1–3 μg/mL) selection were completed using a previously established protocol [ 38 ]. To prepare control wild type (WT) cell line, we transfected TrueGuide™ sgRNA negative control, non-targeting 1 (Invitrogen, Cat.…”

“…Macrophages display different gene expression and protein activity according to duration of LPS exposure, and STAT3 plays an active role in the inflammatory process [ 36 , 37 , 38 ]. We wished to investigate the intracellular inflammatory signaling of STAT3 at several time points during LPS exposure in vitro.…”

Natural products of traditional Chinese medicine treat atherosclerosis by regulating inflammatory and oxidative stress pathways

“…This series of signal transductions promotes the activation of various immune response genes namely, nuclear factor kappa B (NF-κB), transcription factor complex activator protein-1 (AP-1), and interferon regulatory factors (IRFs) and induces the expression of various cytokines and adhesion molecules associated with the inflammatory response. This has become recognized as a pathogenic mechanism of AS (Kim et al, 2018). Oxidative stress and cellular damage activate TLR4, leading to the expression of inflammatory mediators (Zhu et al, 2021).…”

Dietary inclusion of plant ingredients induces epigenetic changes in the intestine of zebrafish

“…Tbk1 is a IκB-related kinase that activates NF-κB after forming a complex with the IκB proteins Tank and Traf2 [54]. Studies also revealed that a high level of Tbk1 triggered an MAPK phosphatase-1-mediated negative feedback pathway to control inflammation [55]. The epigenetic regulation of tkb1 may be involved in controlling the inflammatory response triggered by plant protein-based diets and in maintaining the intestinal homoeostasis in zebrafish.…”