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Dive into the research topics where Jae Hyang Lim is active.

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Featured researches published by Jae Hyang Lim.


Journal of Immunology | 2007

A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

Unhwan Ha; Jae Hyang Lim; Hirofumi Jono; Tomoaki Koga; Amit Srivastava; Richard Malley; Gilles Pagès; Jacques Pouysségur; Jian Dong Li

Epithelial cells represent the first line of host innate defense against invading microbes by elaborating a range of molecules involved in pathogen clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. How mucin is induced in upper respiratory Streptococcus pneumoniae infections is unknown. In this study, we show that pneumolysin is required for up-regulation of MUC5AC mucin via TLR4-dependent activation of ERK in human epithelial cells in vitro and in mice in vivo. Interestingly, a “second wave” of ERK activation appears to be important in mediating MUC5AC induction. Moreover, IκB kinase (IKK) α and IKKβ are distinctly involved in MUC5AC induction via an ERK1-dependent, but IκBα-p65- and p100-p52-independent, mechanism, thereby revealing novel roles for IKKs in mediating up-regulation of MUC5AC mucin by S. pneumoniae.


Journal of Biological Chemistry | 2006

The transforming growth factor-β-smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacteria via a dual mechanism involving functional cooperation with NF-κB and MAPK phosphatase 1-dependent negative cross-talk with p38 MAPK

Fumi Mikami; Jae Hyang Lim; Hajime Ishinaga; Unhwan Ha; He Gu; Tomoaki Koga; Hirofumi Jono; Hirofumi Kai; Jian Dong Li

The transforming growth factor β (TGF-β) pathway represents an important signaling pathway involved in the regulation of diverse biological processes, including cell proliferation, differentiation, and apoptosis. Despite the known role of TGF-βR-mediated signaling in suppressing immune response, its role in regulating human Toll-like receptors (TLRs), key host defense receptors that recognize invading bacterial pathogens, however, remains unknown. Here, we show for the first time that TGF-βR-Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacterium nontypeable Hemophilus influenzae (NTHi) in vitro and in vivo. The positive regulation of TLR2 induction by TGF-βR is mediated via a dual mechanism involving distinct signaling pathways. One mechanism involves functional cooperation between the TGF-βR-Smad3/4 pathway and NF-κB pathway. Another involves MAP kinase phosphatase 1 (MKP-1)-dependent inhibition of p38 MAPK, a known negative regulator for TLR2 induction. Moreover, we showed that TβR-mediated signaling is probably activated by NTHi-derived TGF-β mimicry molecule via an autocrine-independent mechanism. Thus, our study provides new insights into the role of TGF-β signaling in positively regulating host defense response by tightly controlling the expression level of TLR2 during bacterial infections and may lead to new therapeutic strategies for modulating host defense and inflammatory response.


Journal of Biological Chemistry | 2008

MKP1 Regulates the Induction of MUC5AC Mucin by Streptococcus pneumoniae Pneumolysin by Inhibiting the PAK4-JNK Signaling Pathway

Un-Hwan Ha; Jae Hyang Lim; Hyun-Joong Kim; Weihui Wu; Shouguang Jin; Haidong Xu; Jian-Dong Li

Mucosal epithelial cells in the respiratory tract act as the first line of host innate defense against inhaled microbes by producing a range of molecules for clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping the inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. Excess mucin production, however, overwhelms the mucociliary clearance, resulting in defective mucosal defenses. Thus, tight regulation of mucin production is critical for maintaining an appropriate balance between beneficial and detrimental outcomes. Among various mechanisms, negative regulation plays an important role in tightly regulating mucin production. Here we show that the PAK4-JNK signaling pathway acted as a negative regulator for Streptococcus pneumoniae pneumolysin-induced MUC5AC mucin transcription. Moreover pneumolysin also selectively induced expression of MKP1 via a TLR4-dependent MyD88-TRAF6-ERK signaling pathway, which inhibited the PAK4-JNK signaling pathway, thereby leading to up-regulation of MUC5AC mucin production to maintain effective mucosal protection against S. pneumoniae infection. These studies provide novel insights into the molecular mechanisms underlying the tight regulation of mucin overproduction in the pathogenesis of airway infectious diseases and may lead to development of new therapeutic strategies.


Cellular Microbiology | 2008

CYLD is a crucial negative regulator of innate immune response in Escherichia coli pneumonia

Jae Hyang Lim; Unhwan Ha; Chang-Hoon Woo; Haidong Xu; Jian-Dong Li

Bacteraemic pneumonia is a common cause of sepsis in critically ill patients today and is characterized by dysregulation of inflammation. The genetic factors predisposing to bacteraemic pneumonia are not yet fully understood. Innate immunity is pivotal for host defence against invading bacteria, and nuclear factor‐kappa B (NF‐κB) is central to bacteria‐induced inflammation and immune responses. The deubiquitinating enzyme CYLD has been identified as a key negative regulator for NF‐κB. In the present study, we investigated the role of CYLD in innate immune response in Escherichia coli pneumonia. Upon E. coli inoculation, Cyld−/− mice were hypersusceptible to E. coli pneumonia with higher mortality. Innate immune response to E. coli was enhanced in Cyld−/− cells and mice. Cyld−/− cells exhibited enhanced NF‐κB activation upon E. coli inoculation, and the enhanced NF‐κB activation by E. coli was abolished by perturbing IκB kinase (IKK) signalling. Furthermore, IKK inhibitor rescued Cyld−/− mice from lethal infection during E. coli pneumonia along with reduced inflammation. Taken together, these data showed that CYLD acts as a crucial negative regulator for E. coli pneumonia by negatively regulating NF‐κB. These findings provide novel insight into the regulation of bacteraemic pneumonia and related diseases and may help develop novel therapeutic strategies for these diseases.


Molecules and Cells | 2015

Itch E3 ubiquitin ligase positively regulates TGF-β signaling to EMT via Smad7 ubiquitination.

Su-hyun Park; Eun-Ho Jung; Geun-Young Kim; Byung-Chul Kim; Jae Hyang Lim; Chang-Hoon Woo

TGF-β regulates pleiotropic cellular responses including cell growth, differentiation, migration, apoptosis, extracellular matrix production, and many other biological processes. Although non-Smad signaling pathways are being increasingly reported to play many roles in TGF-β-mediated biological processes, Smads, especially receptor-regulated Smads (R-Smads), still play a central mediatory role in TGF-β signaling for epithelial-mesenchymal transition. Thus, the biological activities of R-Smads are tightly regulated at multiple points. Inhibitory Smad (I-Smad also called Smad7) acts as a critical endogenous negative feedback regulator of Smad-signaling pathways by inhibiting R-Smad phosphorylation and by inducing activated type I TGF-β receptor degradation. Roles played by Smad7 in health and disease are being increasingly reported, but the molecular mechanisms that regulate Smad7 are not well understood. In this study, we show that E3 ubiquitin ligase Itch acts as a positive regulator of TGF-β signaling and of subsequent EMT-related gene expression. Interestingly, the Itch-mediated positive regulation of TGF-β signaling was found to be dependent on Smad7 ubiquitination and its subsequent degradation. Further study revealed Itch acts as an E3 ubiquitin ligase for Smad7 polyubiquitination, and thus, that Itch is an important regulator of Smad7 activity and a positive regulator of TGF-β signaling and of TGF-β-mediated biological processes. Accordingly, the study uncovers a novel regulatory mechanism whereby Smad7 is controlled by Itch.


Journal of Biological Chemistry | 2004

NF-κB Is Essential for Induction of CYLD, the Negative Regulator of NF-κB EVIDENCE FOR A NOVEL INDUCIBLE AUTOREGULATORY FEEDBACK PATHWAY

Hirofumi Jono; Jae Hyang Lim; Lin Feng Chen; Haidong Xu; Eirini Trompouki; Zhixing K. Pan; George Mosialos; Jian Dong Li


Biochemical and Biophysical Research Communications | 2004

Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKβ-IκBα-NF-κB signaling pathways

Ran Chen; Jae Hyang Lim; Hirofumi Jono; Xin Xing Gu; Young S. Kim; Carol Basbaum; Timothy F. Murphy; Jian Dong Li


Biochemical and Biophysical Research Communications | 2006

Synergistic activation of NF-κB by nontypeable H. influenzae and S. pneumoniae is mediated by CK2, IKKβ-IκBα, and p38 MAPK

Soo Mi Kweon; Beinan Wang; Davida Rixter; Jae Hyang Lim; Tomoaki Koga; Hajime Ishinaga; Lin Feng Chen; Hirofumi Jono; Haidong Xu; Jian Dong Li


Molecules and Cells | 2017

CHOP Deficiency Ameliorates ERK5 Inhibition-Mediated Exacerbation of Streptozotocin-Induced Hyperglycemia and Pancreatic β-Cell Apoptosis

Chang-Hoon Woo; Kwon Moo Park; Jae Hyang Lim; Jung-Hwa Han; Dae-Hwan Nam


Archive | 2009

Original Article Differential regulation of Streptococcus pneumoniae- induced human MUC5AC mucin expression through distinct MAPK pathways

Jae Hyang Lim; Hyun-Jung Kim; Kensei Komatsu; Un-Hwan Ha; Yuxian Huang; Hirofumi Jono; Soo-Mi Kweon; Jiyun Lee; Xiangbin Xu; Gen-Sheng Zhang; Huahao Shen; Hirofumi Kai; Haidong Xu; Jian Dong Li

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Hirofumi Jono

University of Southern California

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Jian Dong Li

University of Southern California

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Tomoaki Koga

University of Rochester Medical Center

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Hajime Ishinaga

University of Southern California

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Unhwan Ha

University of Southern California

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Hirofumi Kai

University of Southern California

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Jian-Dong Li

Georgia State University

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Xiangbin Xu

University of Rochester

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Chang-Hoon Woo

University of Rochester Medical Center

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