TL1A (TNFSF15) Regulates the Development of Chronic Colitis by Modulating Both T-Helper 1 and T-Helper 17 Activation

doi:10.1053/j.gastro.2008.04.037

Gastroenterology

Volume 135, Issue 2, August 2008, Pages 552-567.e2

https://doi.org/10.1053/j.gastro.2008.04.037 Get rights and content

Background & Aims: TL1A is a tumor necrosis factor–like molecule that mediates a strong costimulation of T-helper (T_H) 1 cells. Expression of TL1A is increased in the mucosa of Crohn's disease patients and murine models of ileitis. The aim of this study was to determine the possible role of TL1A in chronic intestinal inflammation. Methods:We used dextran sodium sulfate (DSS)-induced chronic colitis to investigate the effects of TL1A on the development of colitis. The cytokine profile in the gut-associated lymphoid tissue (GALT) was measured. Neutralizing anti-TL1A antibodies were injected intraperitoneally into DSS-induced chronic colitis and G protein αi2^−/− T-cell transfer colitis models. Severity of colitis was evaluated by body weight, colon length, histology, and cytokine production. Results:DSS-induced chronic colitis was characterized by the infiltration of CD4⁺ T cells. TL1A, death receptor 3, interferon (IFN)-γ, and interleukin (IL)-17 were increased significantly in GALT of DSS-treated mice. TL1A up-regulated both IFN-γ production from T_H1 cells and IL-17 production from T_H17 cells in GALT CD4⁺ T cells. Furthermore, IFN-γ and IL-17 production from CD4⁺ T cells, induced by IL-12 and IL-23 respectively, was enhanced synergistically by combination with TL1A. Anti-TL1A antibody prevented chronic colitis and attenuated established colitis by down-regulation of both T_H1 and T_H17 activation. Conclusions:Our results reveal that TL1A is an important modulator in the development of chronic mucosal inflammation by enhancing T_H1 and T_H17 effector functions. The central role of TL1A represents an attractive, novel therapeutic target for the treatment of Crohn's disease patients.

Section snippets

Mice

C57BL/6 mice were purchased from the Jackson Laboratory (Bar Harbor, ME). Mice were maintained under specific pathogen-free conditions in the Animal Care Facility at Cedars-Sinai Medical Center. Gαi2^−/− (129/Sv background) mice were housed at the University of California, Los Angeles Animal Care Facility. RAG2^−/− mice (129/Sv background) were obtained from the University of California, Los Angeles Department of Radiation Oncology or purchased from Taconic Farms (Germantown, NY). Mice used in

Characterization of DSS-Induced Chronic Colitis

DSS-induced acute colitis has been known as a T-cell–independent model.²⁰ However, in chronic colitis induced by multiple cycles or in the recovery phase of DSS, adaptive immunity plays an important role in the disease process.21, 22 Chronic colitis was induced by administration of 4 cycles of 3% DSS drinking water to C57BL/6 mice. Loss of body weight was first observed at day 5. Maximum weight loss was seen at day 12 and mice regained body weight after 2 cycles of DSS (Figure 1A). Mice were

Discussion

This study shows that TL1A plays a causal role in the development and perpetuation of T-cell–mediated chronic colitis by enhancing both IFN-γ and IL-17 production from mucosal CD4⁺ T cells. TL1A and DR3 were up-regulated significantly in the intestine of DSS-treated mice, which confirms previous studies in human CD and murine ileitis.9, 11 We and others also have shown that TL1A was expressed on monocytes and CD11c^high major histocompatibility complex class II⁺ DCs and transmembrane DR3 was

References (39)

R.B. Sartor
Microbial influences in inflammatory bowel diseases
Gastroenterology
(2008)
T.S. Migone et al.
TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator
Immunity
(2002)
J.L. Prehn et al.
Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation
Clin Immunol
(2004)
L.A. Dieleman et al.
Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice
Gastroenterology
(1994)
M. Veldhoen et al.
TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells
Immunity
(2006)
C.O. Elson et al.
Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice
Gastroenterology
(2007)
R.J. Xavier et al.
Unravelling the pathogenesis of inflammatory bowel disease
Nature
(2007)
W. Strober et al.
The immunology of mucosal models of inflammation
Annu Rev Immunol
(2002)
C.O. Elson et al.
Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota
Immunol Rev
(2005)
D.W. Hommes et al.
Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease
Gut
(2006)

P.J. Mannon et al.

Anti-interleukin-12 antibody for active Crohn's disease

N Engl J Med

(2004)

J.L. Prehn et al.

The T cell costimulator TL1A is induced by Fc{gamma}R signaling in human monocytes and dendritic cells

J Immunol

(2007)

G. Bamias et al.

Role of TL1A and its receptor DR3 in two models of chronic murine ileitis

Proc Natl Acad Sci U S A

(2006)

K.A. Papadakis et al.

Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes

J Immunol

(2005)

M.A. Cassatella et al.

Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis

J Immunol

(2007)

G. Bamias et al.

Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease

J Immunol

(2003)

K.A. Papadakis et al.

TL1A synergizes with IL-12 and IL-18 to enhance IFN-gamma production in human T cells and NK cells

J Immunol

(2004)

Y. Picornell et al.

TNFSF15 is an ethnic-specific IBD gene

Inflamm Bowel Dis

(2007)

K. Yamazaki et al.

Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease

Hum Mol Genet

(2005)

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In this study, we investigated the immunomodulatory effects of wogonin on IBD and its potential mechanisms in vitro and in vivo.
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Hippocampal and gut AMPK activation attenuates enterocolitis-like symptoms and co-occurring depressive-like behavior in ulcerative colitis model mice: Involvement of brain-gut autophagy
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TL1A priming induces a multi-cytokine Th9 cell phenotype that promotes robust allergic inflammation in murine models of asthma
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Multi-cytokine-producing Th9 cells secrete IL-9 and type 2 cytokines and mediate mouse and human allergic inflammation. However, the cytokines that promote a multi-cytokine secreting phenotype have not been defined. Tumor necrosis factor superfamily member TL1A signals through its receptor DR3 to increase IL-9. Here we demonstrate that TL1A increases expression of IL-9 and IL-13 co-expressing cells in murine Th9 cell cultures, inducing a multi-cytokine phenotype. Mechanistically, this is linked to histone modifications allowing for increased accessibility at the Il9 and Il13 loci. We further show that TL1A alters the transcription factor network underlying expression of IL-9 and IL-13 in Th9 cells and increases binding of transcription factors to Il9 and Il13 loci. TL1A-priming enhances the pathogenicity of Th9 cells in murine models of allergic airway disease through the increased expression of IL-9 and IL-13. Lastly, in both chronic and memory-recall models of allergic airway disease, blockade of TL1A signaling decreases the multi-cytokine Th9 cell population and attenuates the allergic phenotype. Taken together, these data demonstrate that TL1A promotes the development of multi-cytokine Th9 cells that drive allergic airway diseases and that targeting pathogenic T helper cell-promoting cytokines could be an effective approach for modifying disease.
Brexpiprazole prevents colitis-induced depressive-like behavior through myelination in the prefrontal cortex
2023, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology including depression. The dextran sulfate sodium (DSS)-treated mice exhibit IBD- and depressive-like phenotypes. A disturbed intestinal environment causes a decrease in serotonin and abnormal myelination in the brain, along with depressive-like behavior in rodents. However, the involvement of these factors in DSS-induced depressive-like behavior in mice remains unclear. In this study, we examined whether myelin proteins in the prefrontal cortex (PFC) and hippocampi were altered in DSS-treated mice, along with the changes in the serotonergic system in the PFC by western blotting and HPLC. The effects of brexpiprazole (Brx), a serotonin modulator, on DSS-induced depressive-like behavior using the tail-suspension test were evaluated. Subsequently, we investigated Brx's effects on the levels of myelin, nodal proteins, and neurotrophic molecules in the PFC with western blotting, and examined the altered node of Ranvier formation by immunohistochemistry. DSS-treated mice showed a reduction in myelin and nodal proteins, dysfunction of the serotonergic system, and impaired formation of the nodes of Ranvier in the PFC. Brx administration prevented the DSS-induced depressive-like behavior and demyelination in the PFC. However, the Brx-mediated effects were inhibited by the selective 5-HT_1A antagonist, WAY100635, or the selective TrkB antagonist, ANA-12. Brx decreased the phosphorylation of ERK, CREB, and TrkB along with the expression of BDNF in the PFC of DSS-treated mice. Moreover, the effects of Brx were blocked by WAY100635. These findings indicated that myelination regulated by the activation of the ERK1/2-CREB-BDNF-TrkB pathway in the PFC may be involved in mediating the antidepressant effects of Brx.
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Tumor necrosis factor (TNF) superfamily member tumor necrosis factor–like protein 1A (TL1A) has been associated with the susceptibility and severity of inflammatory bowel diseases. However, the function of the tumor necrosis factor–like protein 1A and its receptor death receptor 3 (DR3) in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IECs) during intestinal homeostasis, tissue injury, and regeneration.
Clinical phenotype and histologic inflammation were assessed in C57BL/6 (wild-type), Tl1a^-/- and Dr3^-/- mice in dextran sulfate sodium (DSS)-induced colitis. We generated mice with an IEC-specific deletion of DR3 (Dr3^ΔIEC) and assessed intestinal inflammation and epithelial barrier repair. In vivo intestinal permeability was assessed by fluorescein isothiocyanate dextran uptake. Proliferation of IECs was analyzed by bromodeoxyuridine incorporation. Expression of DR3 messenger RNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine ex vivo regenerative potential.
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: Supported by US National Institutes of Health grants R01 DK056328 (S.R.T.) and DK046763 (S.R.T., J.B.).

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Basic—Alimentary TractTL1A (TNFSF15) Regulates the Development of Chronic Colitis by Modulating Both T-Helper 1 and T-Helper 17 Activation

Section snippets

Mice

Characterization of DSS-Induced Chronic Colitis

Discussion

Gastroenterology

Immunity

Clin Immunol

Gastroenterology

Immunity

Gastroenterology

Unravelling the pathogenesis of inflammatory bowel disease

Nature

The immunology of mucosal models of inflammation

Annu Rev Immunol

Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota

Immunol Rev

Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease

Gut

Anti-interleukin-12 antibody for active Crohn's disease

N Engl J Med

The T cell costimulator TL1A is induced by Fc{gamma}R signaling in human monocytes and dendritic cells

J Immunol

Role of TL1A and its receptor DR3 in two models of chronic murine ileitis

Proc Natl Acad Sci U S A

Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes

J Immunol

Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis

J Immunol

Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease

J Immunol

TL1A synergizes with IL-12 and IL-18 to enhance IFN-gamma production in human T cells and NK cells

J Immunol

TNFSF15 is an ethnic-specific IBD gene

Inflamm Bowel Dis

Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease

Hum Mol Genet

Basic—Alimentary Tract
TL1A (TNFSF15) Regulates the Development of Chronic Colitis by Modulating Both T-Helper 1 and T-Helper 17 Activation