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

Abstract

Toll-like receptor 4 (TLR4) signaling is an important therapeutic target to manage lipopolysaccharide (LPS)-induced inflammation. The transcription factor signal transducer and activator of transcription 3 (STAT3) has been identified as an important regulator of various immune-related diseases and has generated interest as a therapeutic target. Here, we investigated the time-dependent roles of STAT3 in LPS-stimulated RAW264.7 macrophages. STAT3 inhibition induced expression of the pro-inflammatory genes iNOS and COX-2 at early time points. STAT3 depletion resulted in regulation of nuclear translocation of nuclear factor (NF)-κB subunits p50 and p65 and IκBα/Akt/PI3K signaling. Moreover, we found that one Src family kinase, Lyn kinase, was phosphorylated in STAT3 knockout macrophages. In addition to using pharmacological inhibition of NF-κB, we found out that STAT3KO activation of NF-κB subunit p50 and p65 and expression of iNOS was significantly inhibited; furthermore, Akt tyrosine kinase inhibitors also inhibited iNOS and COX-2 gene expression during early time points of LPS stimulation, demonstrating an NF-κB- Akt-dependent mechanism. On the other hand, iNOS expression was downregulated after prolonged treatment with LPS. Activation of NF-κB signaling was also suppressed, and consequently, nitric oxide (NO) production and cell invasion were repressed. Overall, our data indicate that STAT3 differentially regulates early- and late-phase TLR4-mediated inflammatory responses.

Essential Role of STAT3 Signaling in Hair Follicle Homeostasis

“…Crosstalk between JAK/STAT and TLR pathways has been suggested in several reports ( 45 – 47 ). In the case of macrophages, STAT3 has been reported to be a negative regulator for TLR4 signaling ( 47 ). Therefore, we concluded that STAT3 signaling plays a role in negatively regulating the inflammatory genes downstream of the TLR pathway in skin epithelial cells.…”

“…This report found that STAT3 signaling negatively regulates the expression of genes controlled by the TLR pathway in skin epithelial cells. Crosstalk between JAK/STAT and TLR pathways has been suggested in several reports (45)(46)(47). In the case of macrophages, STAT3 has been reported to be a negative regulator for TLR4 signaling (47).…”

Effect Mechanism of Electroacupuncture at ST36 on the Injured Extensor Digitorum Longus in the Jumping Rat Model Based on mRNA-Seq Analysis

“…Cytokines, including interleukins (ILs), interferons (IFNs), and hematopoietic growth factors, activate the Janus kinase signal transducer and activator of transcription (JAK/STAT) pathway to elicit downstream effects in responding cells. According to their structural features, CISH is associated with cytokine signaling [ 25 ] acting as an important role in development, differentiation, and function of the immune response.…”

“…Hence, STAT3 has already attracted attention of researchers as an important therapeutic target in several diseases. A number of studies have also shown the importance of STAT3 in the inflammatory response to diseases as well as immune response such as inducing pro-inflammatory gene cyclooxygenase 2 expression to regulate TLR4-mediated inflammation in early and late phases, accelerating the development of colitis by the deficiency of STAT3 in hematopoietic cells leads, and involving in the inflammatory bowel disease and bacterial infections [ 25 , 26 ].…”

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“…Crosstalk between JAK/STAT and TLR pathways has been suggested in several reports (45)(46)(47). In the case of macrophages, STAT3 has been reported to be a negative regulator for TLR4 signaling (47). Therefore, we concluded that STAT3 signaling plays a role in negatively regulating the inflammatory genes downstream of the TLR pathway in skin epithelial cells.…”