PKC-epsilon and TLR4 synergistically regulate resistin-mediated inflammation in human macrophages

Abstract

Background and aims Resistin has been associated with atherosclerotic inflammation and cardiovascular complications. We and others have previously shown that PKC-epsilon (PKCε) is involved in resistin-induced smooth muscle cell (VSMC) dysfunction at a high pathological concentration. This study aimed to evaluate the role and potential pathways of resistin at a physiological concentration, in atherosclerosis-related inflammation. Methods Plasma from patients with atherosclerosis was analyzed for resistin concentration. Patients were divided into tertiles based on resistin levels and cytokines were compared between tertiles. Macrophages were then treated with resistin in the presence or absence of PKCε inhibitor and/or TLR4 blocking-antibody, and their inflammatory state was evaluated with ELISA, RT-PCR, immunocytochemistry, and Western blot. Results We observed significant associations between plasma resistin levels and TNF-α, IL-6, IL-12, MIP-1α, MIP-1β, and CD40L. Our in vitro analyses revealed that resistin activated PKCε via TLR4. This was followed by NF-kB activation and induction of a pro-inflammatory phenotype in macrophages, significantly upregulating CD40, downregulating CD206 and stimulating gene expression and secretion of the inflammatory cytokines, for which we found association in our plasma analysis. Resistin also induced persistent TRAM and CD40L upregulation up to 36 hours after resistin treatment. PKCε and TLR4 inhibitors suppressed gene expression to levels similar to control, especially when used in combination. Conclusions Resistin, at a physiological concentration, exacerbates the inflammatory response of macrophages. PKCε is a key upstream mediator in resistin-induced inflammation that may interact synergistically with TLR4 to promote NF-kB activation, while TRAM is an important signal. PKCε and TRAM may represent novel molecular targets for resistin-associated chronic atherosclerotic inflammation.

Obese subcutaneous adipose tissue impairs human myogenesis, particularly in old skeletal muscle, via resistin-mediated activation of NFκB

“…It is clear from the literature that resistin activates NFκB signaling. Such activation has been demonstrated in the HepG2 cells 36 , human coronary artery endothelial cells 38 and in human macrophages 37 . Importantly, genetic approaches have now established the classical NFκB pathway as a negative regulator of myogenesis.…”

Retracted: Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

“…There are few other reports identifying CAP1 as a bonafide receptor for resistin (Lee et al, ; Munjas et al, ). In contrast, TLR4 appears to be a more widely studied receptor of resistin, in not just human cancer models (Gong et al, ; Wang et al, ) but various disease models as well (Y. Jiang et al, ; Li et al, ; Miao et al, ; Zuniga et al, ). Based on the relative number of reports vouching for these two receptors to be the receptors for resistin, clearly TLR4 seems to be relatively well studied.…”

Genome-wide transcriptional profiling identifies potential signatures in discriminating active tuberculosis from latent infection

“…Previous studies have suggested that RETN is associated with type 2 diabetes [ 30 , 31 ], which indicates that RETN could be involved in the host immune response process. It has been reported that RETN can induce production of pro-inflammatory cytokines and chemokines in PBMCs and, can promote macrophage polarization in an independent process [ 32 – 34 ]. In our study, we found that RETN expression was significantly increased in active TB patients compared to LTBI and HC individuals.…”