Curcumin suppresses NTHi-induced CXCL5 expression via inhibition of positive IKKβ pathway and up-regulation of negative MKP-1 pathway

Abstract

Otitis media (OM) is the most common childhood bacterial infection, and leading cause of conductive hearing loss. Nontypeable Haemophilus influenzae (NTHi) is a major bacterial pathogen for OM. OM characterized by the presence of overactive inflammatory responses is due to the aberrant production of inflammatory mediators including C-X-C motif chemokine ligand 5 (CXCL5). The molecular mechanism underlying induction of CXCL5 by NTHi is unknown. Here we show that NTHi up-regulates CXCL5 expression by activating IKKβ-IκBα and p38 MAPK pathways via NF-κB nuclear translocation-dependent and -independent mechanism in middle ear epithelial cells. Current therapies for OM are ineffective due to the emergence of antibiotic-resistant NTHi strains and risk of side effects with prolonged use of immunosuppressant drugs. In this study, we show that curcumin, derived from Curcuma longa plant, long known for its medicinal properties, inhibited NTHi-induced CXCL5 expression in vitro and in vivo. Curcumin suppressed CXCL5 expression by direct inhibition of IKKβ phosphorylation, and inhibition of p38 MAPK via induction of negative regulator MKP-1. Thus, identification of curcumin as a potential therapeutic for treating OM is of particular translational significance due to the attractiveness of targeting overactive inflammation without significant adverse effects.

Curcumin Inhibits NTHi-Induced MUC5AC Mucin Overproduction in Otitis Media via Upregulation of MAPK Phosphatase MKP-1

“…NTHi was prepared as described previously [13]. For in vitro experiments NTHi was resuspended in DMEM and used at a multiplicity of infection (MOI) of 50.…”

Decreased CXCL5 expression associated with intrauterine adhesions in a rat model and human endometrial tissues

“…After binding with its receptor CXCR2, CXCL5 enables the recruitment of neutrophils followed by the promotion of angiogenesis and the remodeling of connective tissues [18]. Recently, Konduru, A.S. reported that the knockdown of endogenous p65 suppresses CXCL5 gene transcription in vivo [19], indicating that the CXCL5 expression level is regulated by the NF-κB pathway. In contrast, the silence of CXCL5 expression inhibited the NF-κB pathway in cells also has been demonstrated [20].…”

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.…”