Reciprocal IFN-γ and TGF-β responses regulate the occurrence of mucosal inflammation

Strober, Warren; Kelsall, Brian L.; Fuss, Ivan J.; Marth, Thomas; Lúðvíksson, Björn Rúnar; Ehrhardt, Rolf O.; Neurath, Markus F.

doi:10.1016/s0167-5699(97)01000-1

Cited by 382 publications

(205 citation statements)

References 8 publications

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“…In this regard, the enhanced secretion of anti-inflammatory cytokines such as IL-4, IL-10, and TGF-␤ 1 by hepatic CD4 ϩ T cells should be noted. The profile of the lymphokines produced by hepatic CD4 ϩ T cells was similar to that of T cells in GALT after administration of an Ag at a low dose (13,14). Thus, although we do not exclude the possibility that suppressor function by hepatic CD4 ϩ FasL high T cells in the recipient mice was mediated by cytokines, FasL appears to play a major role in the effector phase.…”

Section: Discussionmentioning

confidence: 76%

“…In fact, hepatic sinusoidal endothelial cells and dendritic cells can present Ags (3,4,35). Alternatively, these regulatory T cells can develop in GALT (14) and then migrate to the liver. However, i.p.…”

Section: Discussionmentioning

confidence: 99%

“…The induction mechanism involved in the oral tolerances depends on the dose of Ags administered. Thus, administration of Ags at a low dose leads to the emergence of T cells producing suppressive cytokines, whereas a high dose leads to clonal anergy and deletion of T cells (10,(13)(14)(15). However, in the latter case where a part of the Ag is absorbed in an immunogenic form, it is still largely unknown whether generation of suppressor cells associates with clonal deletion or how T cells residing outside of gut-associated lymphoid tissue (GALT) 3 are involved in the induction of tolerance.…”

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confidence: 99%

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Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

Watanabe

Yoshida

Shirai

et al. 2002

The Journal of Immunology

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Ags administered orally at a high dose are absorbed in immunogenic forms and perfuse the liver, which raises a question regarding the relevance of hepatic lymphocyte activation to the systemic hyporesponsiveness against the ingested Ag. Oral administration of 100 mg of OVA to the mice led to massive cell death of OVA-specific (KJ1-26+) CD4+ T cells by Fas-Fas ligand (FasL)-mediated apoptosis in the liver, which was associated with the emergence of hepatic KJ1-26+CD4+ T cells expressing FasL. Hepatic CD4+ T cells in OVA-fed mice secreted large amounts of IL-4, IL-10, and TGF-β1 upon restimulation in vitro and inhibited T cell proliferation. Adoptive transfer of these hepatic CD4+ T cells to naive mice and subsequent antigenic challenge led to suppression of T cell proliferation as well as IgG Ab responses to OVA; this effect was mostly abrogated by a blocking Ab to FasL. i.p. administration of an Ag at a high dose also generated hepatic CD4+FasL+ T cells with similar cytokine profile as T cells activated by oral administration of Ags at a high dose. Finally, we did not see an increase in FasL+ cells in the hepatic CD4+Vβ8+ T cell subset of MRL/lpr/lpr mice given staphylococcal enterotoxin B, indicating the requirement for Fas-mediated signals. These hepatic CD4+FasL+ regulatory cells may explain the tolerogenic property of the liver and play roles in systemic hyporesponsiveness induced by an Ag administered at a high dose.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

Watanabe

Yoshida

Shirai

et al. 2002

The Journal of Immunology

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“…Previous research has demonstrated the importance of dysregulated T-cell production of IFN-g in the mucosal inflammatory process. [6][7][8] We have previously demonstrated that there are mucosa-specific mechanisms for T-cell cytokine gene regulation of IFN-g expression, which differ from those seen in PBL. 11,[13][14][15]22 Studies by other groups have indicated that regulation of IFN-g gene expression in primary T cells differs from that observed in tumor T-cell lines, and likewise, differs in naïve compared to memory T-cell subsets.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Inappropriate overexpression of IFN-g by activated mucosal T cells is an important contributory factor in the pathogenesis of inflammatory bowel disease (IBD). [6][7][8] In fact, disease severity is correlated with the level of IFN-g expression. 9 The pathways leading to activation of mucosal lamina propria T cells are different from those of peripheral T cells.…”

Section: Introductionmentioning

confidence: 99%

An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells

et al. 2006

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This study examines mucosa-specific regulatory pathways involved in modulation of interferon-g (IFN-g) in lamina propria T cells. Previous studies identified mucosa-specific CD2 cis-elements within the À204 to À108 bp IFNG promoter. Within this region, a single-site nucleotide polymorphism, À179G/T, imparts tumor necrosis factor-a stimulation of IFNG in peripheral blood lymphocytes, and is linked with accelerated AIDS progression. We discovered a putative estrogen response element (ERE) introduced by the À179T, which displays selective activation in peripheral blood mononuclear cells (PBMC) vs lamina propria mononuclear cells (LPMC). Transfection of PBMC with constructs containing the À179G or À179T site revealed CD2-mediated enhancement of the À179T compared to À179G allele, although, in LPMC, a similar level of expression was detected. Electrophoretic mobility shift assay (EMSA) analysis demonstrated CD2-mediated nucleoprotein binding to the À179T but not the À179G in PBMC. In LPMC, binding is constitutive to both À179G and À179T regions. Sequence and EMSA analysis suggests that the À179T allele creates an ERE-like binding site capable of binding recombinant estrogen receptor. Estrogen response element transactivation is enhanced by CD2 signaling, but inhibited by estrogen in PBMC but not in LPMC, although expression of estrogen receptor was similar. This is the first report to describe a potential molecular mechanism responsible for selectively controlling IFN-g production in LPMC.

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Recombinant IFN-γ abrogates allograft tolerance induced by donor-specific blood transfusion by restoring alloantibody production

et al. 1999

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Donor-specific tolerance to heart allograft was induced in adult Lewis rats by pregraft donor-specific blood transfusion (DST). We previously showed that this tolerant state is characterized by a dramatic inhibition of T cell and macrophage activation. In addition, tolerant animals could not mount an efficient anti-donor humoral response whereas transfer of sera from rejecting animals triggered rejection in tolerant animals. This tolerance can be abrogated by daily post-graft administration of recombinant IFN-gamma (rIFN-gamma). To elucidate the mechanisms of action of rIFN-gamma, T cell, macrophage and B cell functions were assessed in allograft recipients. IFN-gamma did not restore the expression of Th1-related cytokine mRNA or the activated macrophage product inducible nitric oxide synthase in allografts. Importantly, rIFN-gamma treatment promptly restored the anti-donor humoral response in DST-treated recipients. We conclude that rIFN-gamma treatment in DST-treated allograft recipients cannot reverse the unresponsive state of Th1 cells and macrophages infiltrating the graft, but can provide B cell help for IgG alloantibody production which is lacking in these animals.

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Reciprocal IFN-γ and TGF-β responses regulate the occurrence of mucosal inflammation

Cited by 382 publications

References 8 publications

Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells

Recombinant IFN-γ abrogates allograft tolerance induced by donor-specific blood transfusion by restoring alloantibody production

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