Induction of beta defensin 2 by NTHi requires TLR2 mediated MyD88 and IRAK-TRAF6-p38MAPK signaling pathway in human middle ear epithelial cells

Lee, Haa Yung; Takeshita, Tamotsu; Shimada, Jun; Akopyan, Arsen; Woo, Jeong Im; Pan, Huiqi; Moon, Sangook; Andalibi, Ali; Park, Rae Kil; Kang, Seung Ho; Kang, Shin Seok; Gellibolian, Robert; Lim, David J.

doi:10.1186/1471-2334-8-87

Cited by 54 publications

(54 citation statements)

References 68 publications

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“…24 Human β-defensin 2 (HBD2) is seen to be up-regulated in the middle ear response to bacteria and cytokines like non-typeable Haemophilus influenzae (NTHi) and interleukin (IL)-1α. 25,26 HBD2 expression occurs in response to NTHi binding to toll-like receptor 2 (TLR2) and subsequent activation of a toll/IL-1 receptor MyD88-IRAK1-TRAF6-MKK3/6-p38 MAP kinase signal transduction pathway. 25,26 Beta-defensin 2 production has been demonstrated to be greatest when the p38 MAP kinase pathway acts synergistically with the MyD88-independent Raf-MEK1/2-ERK MAP kinase pathway stimulated by IL-1α.…”

Section: Epithelial Cellsmentioning

confidence: 99%

“…25,26 HBD2 expression occurs in response to NTHi binding to toll-like receptor 2 (TLR2) and subsequent activation of a toll/IL-1 receptor MyD88-IRAK1-TRAF6-MKK3/6-p38 MAP kinase signal transduction pathway. 25,26 Beta-defensin 2 production has been demonstrated to be greatest when the p38 MAP kinase pathway acts synergistically with the MyD88-independent Raf-MEK1/2-ERK MAP kinase pathway stimulated by IL-1α. 25,26 In addition, the β-defensin 2 production in epithelial cells is up-regulated with exposure to tumor necrosis factor alpha (TNF-α) and lipopolysaccharide (LPS).…”

Section: Epithelial Cellsmentioning

confidence: 99%

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Role of innate immunity in the pathogenesis of otitis media

Mittal

Kodiyan

Gerring

et al. 2014

International Journal of Infectious Diseases

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Summary Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects.

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Section: Epithelial Cellsmentioning

confidence: 99%

Section: Epithelial Cellsmentioning

confidence: 99%

Role of innate immunity in the pathogenesis of otitis media

Mittal

Kodiyan

Gerring

et al. 2014

International Journal of Infectious Diseases

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“…but Not TRAF6-In an effort to determine the proximal events leading to N-Ras activation, RNA interference was used to selectively target TLR4 and TRAF6, an adaptor molecule known to transduce signals from TLRs to both NFB and MAPKs (31). We have previously demonstrated that TLR4 depletion by siRNAs suppresses TLR4 protein expression and diminishes NFB activation in the presence of TLR4 ligands (27).…”

Section: Lps-induced Cholangiocyte N-ras Activation Requires Tlr4mentioning

confidence: 99%

Cholangiocyte N-Ras Protein Mediates Lipopolysaccharide-induced Interleukin 6 Secretion and Proliferation

O’Hara

Splinter

Trussoni

et al. 2011

Journal of Biological Chemistry

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Cholangiocytes, the epithelial cells lining the bile ducts in the liver, are periodically exposed to potentially injurious microbes and/or microbial products. As a result, cholangiocytes actively participate in microbe-associated, hepatic proinflammatory responses. We previously showed that infection of cultured human cholangiocytes with the protozoan parasite, Cryptosporidium parvum, or treatment with Gram-negative bacteria-derived LPS, activates NFB in a myeloid differentiation 88 (MyD88)-dependent manner. Here, we describe a novel signaling pathway initiated by Toll-like receptors (TLRs) involving the small GTPase, Ras, that mediates cholangiocyte proinflammatory cytokine production and induction of cholangiocyte proliferation. Using cultured human cholangiocytes and a Ras activation assay, we found that agonists of plasma membrane TLRs (TLR 1, 2, 4, 5, and 6) rapidly (<10 min) activated N-Ras, but not other p21 Ras isoforms, resulting in the rapid (<15 min) phosphorylation of the downstream Ras effector, ERK1/2. RNA interference-induced depletion of TRAF6, a downstream effector of MyD88 and known activator of MAPK signaling, had no effect on N-Ras activation. Following N-Ras activation the proinflammatory cytokine, IL6, is rapidly secreted. Using a luciferase reporter, we demonstrated that LPS treatment induced IL6 promoter-driven luciferase which was suppressed using MEK/ ERK pharmacologic inhibitors (PD98059 or U0126) and RNAiinduced depletion of N-Ras. Finally, we showed that LPS increased cholangiocyte proliferation (1.5-fold), which was inhibited by depletion of N-Ras; TLR agonist-induced proliferation was also inhibited following pretreatment with an IL6 receptor-blocking antibody. Together, our results support a novel signaling axis involving microbial activation of N-Ras likely involved in the cholangiocyte pathogen-induced proinflammatory response.Intrahepatic bile ducts form a complex three-dimensional tubular network that modifies the composition of bile and serves as a conduit for delivery of bile to the duodenum. Although bile is thought to be sterile under normal physiological conditions, biliary epithelial cells lining bile ducts (cholangiocytes) are periodically exposed to potentially pathogenic organisms or products derived from these microbes (1-4). Indeed, cholangiocytes are exposed to bacteria (5-9), viruses (10 -12), and parasites (13-16). Cholangiocyte pathogen recognition promotes innate and adaptive immune responses (4, 17-19) through the expression of adhesion molecules (20 -22) and the secretion of cytokines/chemokines (23, 24) and antimicrobial peptides (18, 23). Thus, cholangiocytes once thought of as an exclusively secretory/absorptive epithelium with a primary role in bile modification, are now recognized as important in the hepatic proinflammatory response to microorganisms or microbially derived products. However, the molecular pathways regulating cholangiocyte recognition and response to microbial insults are obscure and are the focus of the work presented here. Toll-like r...

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“…HMEEC-1 cells were found to up-regulate beta defensin 2 in response to interleukin 1 alpha (IL-1a) via a Srcdependent Raf-MEK1/2-ERK signaling pathway [34]. We also found that nontypeable H. influenzae-induced up-regulation of beta defensin 2 requires a TLR2/MyD88-dependent p38 MAP kinase pathway [35]. As shown in Fig.…”

Section: Induction Of Antimicrobial Agentsmentioning

confidence: 57%

“…Moreover, we demonstrated that TLR2 is involved in nontypeable H. influenzae-induced NF-kB activation through the TAK1-dependent NIK-IKK-IKB and MKK3/ 6-p38 MAP kinase signaling pathways [39]. In addition, we found the involvement of TLR2 in the recognition of nontypeable H. influenzae molecules, resulting in induction of beta defensin 2 [35].…”

Section: Expression Of Toll-like Receptorsmentioning

confidence: 68%