Limits...
Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease.

Kontoyiannis D, Boulougouris G, Manoloukos M, Armaka M, Apostolaki M, Pizarro T, Kotlyarov A, Forster I, Flavell R, Gaestel M, Tsichlis P, Cominelli F, Kollias G - J. Exp. Med. (2002)

Bottom Line: Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell-derived TNF can exhibit full pathogenic capacity.Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase-deficient genetic background.Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

View Article: PubMed Central - PubMed

Affiliation: Institute for Immunology, Biomedical Sciences Research Center "Al. Fleming," Vari 166-72, Greece. Division of Gastroenterology and Hepatology, University of Virginia Health Sciences Center, Charlottesville, VA 22906, USA.

ABSTRACT
Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (Tnf(Delta)(ARE) mouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon gamma and requires the function of CD8(+) T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell-derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor-deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow-derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase-deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

Show MeSH

Related in: MedlinePlus

TNF individually targets hemopoietic and stromal components to induce IBD. Representative photomicrographs of ileal sections from bone marrow–reconstituted mice. (A) Tnf+/+ bone marrow into Tnf+/+ recipient, (B) TnfΔARE/+ bone marrow into Tnf+/+ recipient, (C) anti-TNF–treated control, (D) Tnf+/+ bone marrow into Tnf ΔARE/+ recipient (refer to Materials and Methods and text for details), (E) TnfΔ/Δ TNFRI/II−/− bone marrow into Tnf+/+ recipient, and (F) TnfΔARE/+ bone marrow into TNFRI/II−/− recipient. Paraffin sections stained with hematoxylin and eosin. ×100.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2196068&req=5

fig4: TNF individually targets hemopoietic and stromal components to induce IBD. Representative photomicrographs of ileal sections from bone marrow–reconstituted mice. (A) Tnf+/+ bone marrow into Tnf+/+ recipient, (B) TnfΔARE/+ bone marrow into Tnf+/+ recipient, (C) anti-TNF–treated control, (D) Tnf+/+ bone marrow into Tnf ΔARE/+ recipient (refer to Materials and Methods and text for details), (E) TnfΔ/Δ TNFRI/II−/− bone marrow into Tnf+/+ recipient, and (F) TnfΔARE/+ bone marrow into TNFRI/II−/− recipient. Paraffin sections stained with hematoxylin and eosin. ×100.

Mentions: To confirm the tissue origin of TNF-producing cells that support the development of TNF-mediated IBD and to examine whether non-bone marrow–residing cells may also contribute pathogenic TNF loads, we performed a series of bone marrow engraftment experiments into lethally irradiated recipients. When bone marrow from TnfΔARE/+ mice was transplanted into lethally irradiated (B6,129) Tnf+/+ mice, the majority of the recipients exhibited weight loss 4–6 wk after transplantation (not depicted) and fully developed IBD 10–12 wk after transplantation. The disease borne all the pathological hallmarks of the donor's disease (Table II and Fig. 4 B), including the accumulation of activated CD8+ T cells (not depicted). In contrast, none of the Tnf+/+ recipients of Tnf+/+ bone marrow developed signs of intestinal pathology (Table II and Fig. 4 A). To examine whether radio-resistant TnfΔAREstromal cells suffice to induce IBD, we transplanted Tnf+/+ bone marrow into irradiated TnfΔARE/+ mice. In this case, and to prohibit the development of IBD in the host before transplantation, TnfΔARE/+ mice were treated with anti-TNF antibody before irradiation and were kept without antibody administration after reconstitution (refer to Materials and Methods). Nonirradiated control groups treated with anti-TNF antibody until the age of reconstitution of the test groups developed full IBD 9 wk after the removal of the antibody (Fig. 4 C). In sharp contrast and at this same age, irradiated TnfΔARE/+ mice reconstituted with Tnf+/+ bone marrow showed mild signs of villus blunting but did not develop intestinal inflammation (Fig. 4 D). Taken together, these findings indicate that bone marrow–derived TNF producers such as myeloid cells and/or T lymphocytes, but not tissue stroma cells, constitute cellular sources of TNF with full independent capacity for inducing IBD.


Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease.

Kontoyiannis D, Boulougouris G, Manoloukos M, Armaka M, Apostolaki M, Pizarro T, Kotlyarov A, Forster I, Flavell R, Gaestel M, Tsichlis P, Cominelli F, Kollias G - J. Exp. Med. (2002)

TNF individually targets hemopoietic and stromal components to induce IBD. Representative photomicrographs of ileal sections from bone marrow–reconstituted mice. (A) Tnf+/+ bone marrow into Tnf+/+ recipient, (B) TnfΔARE/+ bone marrow into Tnf+/+ recipient, (C) anti-TNF–treated control, (D) Tnf+/+ bone marrow into Tnf ΔARE/+ recipient (refer to Materials and Methods and text for details), (E) TnfΔ/Δ TNFRI/II−/− bone marrow into Tnf+/+ recipient, and (F) TnfΔARE/+ bone marrow into TNFRI/II−/− recipient. Paraffin sections stained with hematoxylin and eosin. ×100.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196068&req=5

fig4: TNF individually targets hemopoietic and stromal components to induce IBD. Representative photomicrographs of ileal sections from bone marrow–reconstituted mice. (A) Tnf+/+ bone marrow into Tnf+/+ recipient, (B) TnfΔARE/+ bone marrow into Tnf+/+ recipient, (C) anti-TNF–treated control, (D) Tnf+/+ bone marrow into Tnf ΔARE/+ recipient (refer to Materials and Methods and text for details), (E) TnfΔ/Δ TNFRI/II−/− bone marrow into Tnf+/+ recipient, and (F) TnfΔARE/+ bone marrow into TNFRI/II−/− recipient. Paraffin sections stained with hematoxylin and eosin. ×100.
Mentions: To confirm the tissue origin of TNF-producing cells that support the development of TNF-mediated IBD and to examine whether non-bone marrow–residing cells may also contribute pathogenic TNF loads, we performed a series of bone marrow engraftment experiments into lethally irradiated recipients. When bone marrow from TnfΔARE/+ mice was transplanted into lethally irradiated (B6,129) Tnf+/+ mice, the majority of the recipients exhibited weight loss 4–6 wk after transplantation (not depicted) and fully developed IBD 10–12 wk after transplantation. The disease borne all the pathological hallmarks of the donor's disease (Table II and Fig. 4 B), including the accumulation of activated CD8+ T cells (not depicted). In contrast, none of the Tnf+/+ recipients of Tnf+/+ bone marrow developed signs of intestinal pathology (Table II and Fig. 4 A). To examine whether radio-resistant TnfΔAREstromal cells suffice to induce IBD, we transplanted Tnf+/+ bone marrow into irradiated TnfΔARE/+ mice. In this case, and to prohibit the development of IBD in the host before transplantation, TnfΔARE/+ mice were treated with anti-TNF antibody before irradiation and were kept without antibody administration after reconstitution (refer to Materials and Methods). Nonirradiated control groups treated with anti-TNF antibody until the age of reconstitution of the test groups developed full IBD 9 wk after the removal of the antibody (Fig. 4 C). In sharp contrast and at this same age, irradiated TnfΔARE/+ mice reconstituted with Tnf+/+ bone marrow showed mild signs of villus blunting but did not develop intestinal inflammation (Fig. 4 D). Taken together, these findings indicate that bone marrow–derived TNF producers such as myeloid cells and/or T lymphocytes, but not tissue stroma cells, constitute cellular sources of TNF with full independent capacity for inducing IBD.

Bottom Line: Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell-derived TNF can exhibit full pathogenic capacity.Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase-deficient genetic background.Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

View Article: PubMed Central - PubMed

Affiliation: Institute for Immunology, Biomedical Sciences Research Center "Al. Fleming," Vari 166-72, Greece. Division of Gastroenterology and Hepatology, University of Virginia Health Sciences Center, Charlottesville, VA 22906, USA.

ABSTRACT
Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (Tnf(Delta)(ARE) mouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon gamma and requires the function of CD8(+) T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell-derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor-deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow-derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase-deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

Show MeSH
Related in: MedlinePlus