Resveratrol suppresses NTHi-induced inflammation via up-regulation of the negative regulator MyD88 short

Abstract

Upper respiratory tract inflammatory diseases such as asthma and chronic obstructive pulmonary diseases (COPD) affect more than one-half billion people globally and are characterized by chronic inflammation that is often exacerbated by respiratory pathogens such as nontypeable Haemophilus influenzae (NTHi). The increasing numbers of antibiotic-resistant bacterial strains and the limited success of currently available pharmaceuticals used to manage the symptoms of these diseases present an urgent need for the development of novel anti-inflammatory therapeutic agents. Resveratrol has long been thought as an interesting therapeutic agent for various diseases including inflammatory diseases. However, the molecular mechanisms underlying its anti-inflammatory properties remain largely unknown. Here we show for the first time that resveratrol decreases expression of pro-inflammatory mediators in airway epithelial cells and in the lung of mice by enhancing NTHi-induced MyD88 short, a negative regulator of inflammation, via inhibition of ERK1/2 activation. Furthermore, resveratrol inhibits NTHi-induced ERK1/2 phosphorylation by increasing MKP-1 expression via a cAMP-PKA-dependent signaling pathway. Finally, we show that resveratrol has anti-inflammatory effects post NTHi infection, thereby demonstrating its therapeutic potential. Together these data reveal a novel mechanism by which resveratrol alleviates NTHi-induced inflammation in airway disease by up-regulating the negative regulator of inflammation MyD88s.

Pathobiological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies

“…In a separate study, treatment with resveratrol reduced the expression of proinflammatory cytokines (IL-17, IL-6, TNF-α, and TGF-β) in the bronchoalveolar lavage fluid (BALF) of mice exposed to cigarette smoke. Along with this, resveratrol treatment also attenuated the cigarette smokeinduced fibrotic response and mucus hypersecretion in the lungs (Andrews et al, 2016). A recent study in rats also confirmed the efficacy of resveratrol in COPD, and that the beneficial effect of resveratrol may be exerted via the SIRT1 and PGC-1α axis (Wang, Li, Li, Miao, & Xiao, 2017).…”

“…The beneficial effects of resveratrol appear to be AMPKdependent, as mice deficient of this metabolic sensor are no longer protected from metabolic derangement induced by high fat feeding despite the administration of resveratrol (Um et al, 2010). In the context of COPD, resveratrol administration to mice has been shown to alleviate Haemophilus influenzae-induced inflammation of the airway by upregulating the negative regulator of inflammation MyD88 short (MyD88s) (Andrews, Matsuyama, Lee, & Li, 2016). In a separate study, treatment with resveratrol reduced the expression of proinflammatory cytokines (IL-17, IL-6, TNF-α, and TGF-β) in the bronchoalveolar lavage fluid (BALF) of mice exposed to cigarette smoke.…”

Receptor Interacting Protein-2 acts as negative regulator for nontypeable Haemophilus influenzae-induced mucin MUC5AC expression

“…Western blot procedures were previously described [2][3][4][12][13][14][15][16][17]. Western blots were performed using whole-cell extracts, separated on 8-10 % SDS-PAGE gels, and transferred to polyvinylidene difluoride we hypothesized that RIP-2 may play a critical role in regulating mucin production [22].…”

“…NTHi were grown as previously described [12][13][14][15][16]. For in vitro experiments, NTHi was resuspended in PBS and used at a multiplicity of infection (MOI) of 50.…”

“…Total RNA extraction and RT-qPCR were performed as previously described [2][3][4][12][13][14][15][16][17]. The relative quantities of mRNAs were determined by using the comparative Ct method and were normalized by using human cyclophilin for in vitro or mouse glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for in vivo as endogenous controls.…”