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Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells.

Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO - J. Exp. Med. (2008)

Bottom Line: IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro.TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic.Treatment of macrophages with rTNF also inhibited p40 production in vitro.

View Article: PubMed Central - PubMed

Affiliation: Kennedy Institute of Rheumatology Division, Imperial College London, London, W6 8LH, England, UK.

ABSTRACT
IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro. The aim of this study was to assess the impact of TNF inhibition on IL-17 production in collagen-induced arthritis, a model of RA. TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic. Th1 and Th17 cell populations were also expanded in collagen-immunized TNFR p55(-/-) but not p75(-/-) mice. The expression of IL-12/IL-23 p40 was up-regulated in lymph nodes (LN) from p55(-/-) mice, and the expansion of Th1/Th17 cells was abrogated by blockade of p40. Treatment of macrophages with rTNF also inhibited p40 production in vitro. These findings indicate that at least one of the ways in which TNF regulates Th1/Th17 responses in arthritis is by down-regulating the expression of p40. Finally, although TNF blockade increased numbers of Th1 and Th17 cells in LN, it inhibited their accumulation in the joint, thereby providing an explanation for the paradox that anti-TNF therapy ameliorates arthritis despite increasing numbers of pathogenic T cells.

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Amplification of Th17 and Th1 cell activity in p55 TNFR−/− mice. LN cells from WT, p55 TNFR−/−, and p75 TNFR−/− mice were taken 14 d after immunization with type II collagen in CFA. (A) LN cells were either unstimulated or stimulated with collagen or with anti-CD3 mAb, and the level of proliferation was determined by [3H]thymidine incorporation. The percentage of CD4+ T cells in the LN was determined by flow cytometry on day 14 after immunization. (B) Levels of IL-17 and IFNγ were determined by ELISA. (C) The proportion of CD4+ cells in the LN producing IL-17 and IFNγ were determined by flow cytometry. Histograms show mean ± SEM (n = 8). *, P < 0.05; **, P < 0.01. Data are representative of two experiments.
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fig2: Amplification of Th17 and Th1 cell activity in p55 TNFR−/− mice. LN cells from WT, p55 TNFR−/−, and p75 TNFR−/− mice were taken 14 d after immunization with type II collagen in CFA. (A) LN cells were either unstimulated or stimulated with collagen or with anti-CD3 mAb, and the level of proliferation was determined by [3H]thymidine incorporation. The percentage of CD4+ T cells in the LN was determined by flow cytometry on day 14 after immunization. (B) Levels of IL-17 and IFNγ were determined by ELISA. (C) The proportion of CD4+ cells in the LN producing IL-17 and IFNγ were determined by flow cytometry. Histograms show mean ± SEM (n = 8). *, P < 0.05; **, P < 0.01. Data are representative of two experiments.

Mentions: The results show conclusively that inhibition of Th1/Th17 responses occurs via the p55 and not the p75 TNF receptor. Thus, the production of IL-17 and IFNγ was dramatically higher in collagen or anti-CD3 mAb–stimulated LN cell cultures from p55−/− mice compared with either WT or p75−/− mice (Fig. 2 A). Further analysis by flow cytometry confirmed that the proportion of CD4+ T cells producing IL-17 and IFNγ in the LN of p55−/− mice was significantly greater than in those from WT or p75−/− mice (Fig. 2 B). However, increased IFNγ and IL-17 responses were not observed in anti-CD3–stimulated LN cells from nonimmunized p55−/− mice (Fig. 2, A and B), indicating that the T cells were not skewed toward Th1/Th17 responses before immunization. The percentage of CD4+ cells in immunized WT mice coexpressing IFNγ and IL-17 was low (∼0.1%) and was not altered in p55−/− or p75−/− mice.


Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells.

Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO - J. Exp. Med. (2008)

Amplification of Th17 and Th1 cell activity in p55 TNFR−/− mice. LN cells from WT, p55 TNFR−/−, and p75 TNFR−/− mice were taken 14 d after immunization with type II collagen in CFA. (A) LN cells were either unstimulated or stimulated with collagen or with anti-CD3 mAb, and the level of proliferation was determined by [3H]thymidine incorporation. The percentage of CD4+ T cells in the LN was determined by flow cytometry on day 14 after immunization. (B) Levels of IL-17 and IFNγ were determined by ELISA. (C) The proportion of CD4+ cells in the LN producing IL-17 and IFNγ were determined by flow cytometry. Histograms show mean ± SEM (n = 8). *, P < 0.05; **, P < 0.01. Data are representative of two experiments.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2571924&req=5

fig2: Amplification of Th17 and Th1 cell activity in p55 TNFR−/− mice. LN cells from WT, p55 TNFR−/−, and p75 TNFR−/− mice were taken 14 d after immunization with type II collagen in CFA. (A) LN cells were either unstimulated or stimulated with collagen or with anti-CD3 mAb, and the level of proliferation was determined by [3H]thymidine incorporation. The percentage of CD4+ T cells in the LN was determined by flow cytometry on day 14 after immunization. (B) Levels of IL-17 and IFNγ were determined by ELISA. (C) The proportion of CD4+ cells in the LN producing IL-17 and IFNγ were determined by flow cytometry. Histograms show mean ± SEM (n = 8). *, P < 0.05; **, P < 0.01. Data are representative of two experiments.
Mentions: The results show conclusively that inhibition of Th1/Th17 responses occurs via the p55 and not the p75 TNF receptor. Thus, the production of IL-17 and IFNγ was dramatically higher in collagen or anti-CD3 mAb–stimulated LN cell cultures from p55−/− mice compared with either WT or p75−/− mice (Fig. 2 A). Further analysis by flow cytometry confirmed that the proportion of CD4+ T cells producing IL-17 and IFNγ in the LN of p55−/− mice was significantly greater than in those from WT or p75−/− mice (Fig. 2 B). However, increased IFNγ and IL-17 responses were not observed in anti-CD3–stimulated LN cells from nonimmunized p55−/− mice (Fig. 2, A and B), indicating that the T cells were not skewed toward Th1/Th17 responses before immunization. The percentage of CD4+ cells in immunized WT mice coexpressing IFNγ and IL-17 was low (∼0.1%) and was not altered in p55−/− or p75−/− mice.

Bottom Line: IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro.TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic.Treatment of macrophages with rTNF also inhibited p40 production in vitro.

View Article: PubMed Central - PubMed

Affiliation: Kennedy Institute of Rheumatology Division, Imperial College London, London, W6 8LH, England, UK.

ABSTRACT
IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro. The aim of this study was to assess the impact of TNF inhibition on IL-17 production in collagen-induced arthritis, a model of RA. TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic. Th1 and Th17 cell populations were also expanded in collagen-immunized TNFR p55(-/-) but not p75(-/-) mice. The expression of IL-12/IL-23 p40 was up-regulated in lymph nodes (LN) from p55(-/-) mice, and the expansion of Th1/Th17 cells was abrogated by blockade of p40. Treatment of macrophages with rTNF also inhibited p40 production in vitro. These findings indicate that at least one of the ways in which TNF regulates Th1/Th17 responses in arthritis is by down-regulating the expression of p40. Finally, although TNF blockade increased numbers of Th1 and Th17 cells in LN, it inhibited their accumulation in the joint, thereby providing an explanation for the paradox that anti-TNF therapy ameliorates arthritis despite increasing numbers of pathogenic T cells.

Show MeSH
Related in: MedlinePlus