Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy

Wang, Jing H.; Anders, Robert A.; Wu, Qiang; Peng, Dacheng; Cho, Judy H.; Sun, Yonglian; Karaliukas, Reda; Kang, Hyung‐Sik; Turner, Jerrold R.; Fu, Yang–Xin

doi:10.1172/jci200420096

Cited by 36 publications

(42 citation statements)

References 38 publications

(31 reference statements)

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“…(b) Recombinant LIGHT can directly costimulate T cell responses (21). (c) Mice expressing the LIGHT transgene on the T cell lineage exhibited severe T cell-mediated inflammation and autoimmune diseases (9,11). (d) Blockade of LIGHT by HVEM-Ig reduced T cell proliferation and the incidences of T cell-mediated diseases (11).…”

Section: Discussionmentioning

confidence: 99%

“…LIGHT is a potent T cell costimulatory molecule that appears to interact with the herpesvirus entry mediator (HVEM) expressed on T cells (5,6,8). Unlike most other costimulatory molecules delivering signals from APCs, the upregulation of LIGHT on T cells enhanced T cell-mediated immunity and promoted autoimmune diseases and inflammation (9)(10)(11). Local expression of LIGHT on tumor tissues induced a robust expansion and activation of T cells that led to the rejection of local and distal tumors (12).…”

Section: Introductionmentioning

confidence: 99%

“…Transient transfection of HVEM into human 293 cells caused marked activation of NF-κB, a transcriptional regulator of multiple immunomodulatory and inflammatory genes (16). Recent studies have suggested that LIGHT-HVEM signaling is required for stronger T cell-mediated immunity (9)(10)(11)17). To directly study the essential role of HVEM in T cell activation, we generated HVEM -/-mice.…”

Section: Introductionmentioning

confidence: 99%

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The role of herpesvirus entry mediator as a negative regulator of T cell–mediated responses

Wang¹,

Subudhi²,

Anders³

et al. 2005

J. Clin. Invest.

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101

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Herpesvirus entry mediator (HVEM), a TNF receptor superfamily member, has been previously described as a T cell costimulatory receptor. Surprisingly, HVEM -/-T cells showed enhanced responses to in vitro concanavalin A (ConA) stimulation when compared with WT T cells. Consistent with these findings, HVEM -/-mice exhibited increased morbidity and mortality as compared with WT mice in a model of ConA-mediated T cell-dependent autoimmune hepatitis. HVEM -/-mice produced higher levels of multiple cytokines, which were dependent on the presence of CD4 + T cells. Furthermore, HVEM -/-mice were more susceptible to MOG peptide-induced experimental autoimmune encephalopathy, and they showed increased T cell proliferation and cytokine production in response to antigen-specific challenge. Taken together, our data revealed an unexpected regulatory role of HVEM in T cell-mediated immune responses and autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of herpesvirus entry mediator as a negative regulator of T cell–mediated responses

Wang¹,

Subudhi²,

Anders³

et al. 2005

J. Clin. Invest.

Self Cite

101

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“…In particular, we focused on 3 cytokines that have been implicated in epithelial barrier dysfunction, diarrhea, or intestinal inflammatory disease: IFN-g, TNF, and the TNF superfamily member LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry mediator on T cells) (6)(7)(8)(9)(10)(11). However, the effects of these cytokines on intestinal physiology in vivo have not been reported.…”

Section: Introductionmentioning

confidence: 99%

Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo

Clayburgh¹,

Musch²,

Leitges³

et al. 2006

Journal of Clinical Investigation

192

189

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Acute T cell-mediated diarrhea is associated with increased mucosal expression of proinflammatory cytokines, including the TNF superfamily members TNF and LIGHT. While we have previously shown that epithelial barrier dysfunction induced by myosin light chain kinase (MLCK) is required for the development of diarrhea, MLCK inhibition does not completely restore water absorption. In contrast, although TNF-neutralizing antibodies completely restore water absorption after systemic T cell activation, barrier function is only partially corrected. This suggests that, while barrier dysfunction is critical, other processes must be involved in T cell-mediated diarrhea. To define these processes in vivo, we asked whether individual cytokines might regulate different events in T cell-mediated diarrhea. Both TNF and LIGHT caused MLCK-dependent barrier dysfunction. However, while TNF caused diarrhea, LIGHT enhanced intestinal water absorption. Moreover, TNF, but not LIGHT, inhibited Na + absorption due to TNF-induced internalization of the brush border Na + /H + exchanger NHE3. LIGHT did not cause NHE3 internalization. PKCa activation by TNF was responsible for NHE3 internalization, and pharmacological or genetic PKCa inhibition prevented NHE3 internalization, Na + malabsorption, and diarrhea despite continued barrier dysfunction. These data demonstrate the necessity of coordinated Na + malabsorption and barrier dysfunction in TNF-induced diarrhea and provide insight into mechanisms of intestinal water transport.

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“…Although it has been shown in vitro that LIGHT induces apoptosis in several tumor cell lines, there are conflicting reports in regard to the specific receptor mediating this effect (9,10). Recent studies have suggested a potential role of LIGHT in inflammatory diseases including atherosclerosis (11), arthritis (12), IgA nephropathy (13), and inflammatory bowel disease (14). Despite these lines of investigation, the mechanism by which LIGHT mediates inflammatory responses remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis

Anand

Wang

Yoshimura

et al. 2006

Journal of Clinical Investigation

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LIGHT is an important costimulatory molecule for T cell immunity. Recent studies have further implicated its role in innate immunity and inflammatory diseases, but its cellular and molecular mechanisms remain elusive. We report here that LIGHT is upregulated and functions as a proinflammatory cytokine in 2 independent experimental hepatitis models, induced by concanavalin A and Listeria monocytogenes. Molecular mutagenesis studies suggest that soluble LIGHT protein produced by cleavage from the cell membrane plays an important role in this effect through the interaction with the lymphotoxin-β receptor (LTβR) but not herpes virus entry mediator. NK1.1 + T cells contribute to the production, but not the cleavage or effector functions, of soluble LIGHT. Importantly, treatment with a mAb that specifically interferes with the LIGHT-LTβR interaction protects mice from lethal hepatitis. Our studies thus identify a what we believe to be a novel function of soluble LIGHT in vivo and offer a potential target for therapeutic interventions in hepatic inflammatory diseases.

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Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy

Abstract: Whether and how T cells contribute to the pathogenesis of immunoglobulin

Cited by 36 publications

References 38 publications

The role of herpesvirus entry mediator as a negative regulator of T cell–mediated responses

The role of herpesvirus entry mediator as a negative regulator of T cell–mediated responses

Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo

Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis

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