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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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Blockade of IL-12/IL-23 blocks the expansion of Th1/Th17 cells. (A–C) LN cells from immunized WT (white bars) or p55 TNFR−/− (gray bars) mice treated with control Ig (Ig) or rat anti–mouse p40 Ab (p40) were either unstimulated or stimulated with collagen or anti-CD3 mAb. Levels of IL-17 (A) and IFNγ (B) were determined by ELISA, and the proportion of CD4+ cells in the LN producing IL-17 and IFNγ were determined by flow cytometry (C). Histograms show mean ± SEM (n = 5). *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data are representative of two experiments.
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fig4: Blockade of IL-12/IL-23 blocks the expansion of Th1/Th17 cells. (A–C) LN cells from immunized WT (white bars) or p55 TNFR−/− (gray bars) mice treated with control Ig (Ig) or rat anti–mouse p40 Ab (p40) were either unstimulated or stimulated with collagen or anti-CD3 mAb. Levels of IL-17 (A) and IFNγ (B) were determined by ELISA, and the proportion of CD4+ cells in the LN producing IL-17 and IFNγ were determined by flow cytometry (C). Histograms show mean ± SEM (n = 5). *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data are representative of two experiments.

Mentions: We then questioned whether inhibition of IL-12/IL-23 p40 activity in p55−/− mice would result in a reduction of IFNγ/IL-17 production and reduced numbers of Th1/Th17 cells. Treatment with a blocking anti–mouse p40 mAb in p55−/− mice from the day of immunization to day 14 after immunization partially or completely abrogated both the increase in IL-17 and IFNγ production and the expansion of CD4+IL-17+ and CD4+IFNγ+ cells (Fig. 4). These findings strongly suggest that at least one of the mechanisms by which TNFα influences the development and/or survival of Th1 and Th17 cells is by inhibition of IL-12/IL-23 p40 expression, although other mechanisms may also be involved.


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)

Blockade of IL-12/IL-23 blocks the expansion of Th1/Th17 cells. (A–C) LN cells from immunized WT (white bars) or p55 TNFR−/− (gray bars) mice treated with control Ig (Ig) or rat anti–mouse p40 Ab (p40) were either unstimulated or stimulated with collagen or anti-CD3 mAb. Levels of IL-17 (A) and IFNγ (B) were determined by ELISA, and the proportion of CD4+ cells in the LN producing IL-17 and IFNγ were determined by flow cytometry (C). Histograms show mean ± SEM (n = 5). *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data are representative of two experiments.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571924&req=5

fig4: Blockade of IL-12/IL-23 blocks the expansion of Th1/Th17 cells. (A–C) LN cells from immunized WT (white bars) or p55 TNFR−/− (gray bars) mice treated with control Ig (Ig) or rat anti–mouse p40 Ab (p40) were either unstimulated or stimulated with collagen or anti-CD3 mAb. Levels of IL-17 (A) and IFNγ (B) were determined by ELISA, and the proportion of CD4+ cells in the LN producing IL-17 and IFNγ were determined by flow cytometry (C). Histograms show mean ± SEM (n = 5). *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data are representative of two experiments.
Mentions: We then questioned whether inhibition of IL-12/IL-23 p40 activity in p55−/− mice would result in a reduction of IFNγ/IL-17 production and reduced numbers of Th1/Th17 cells. Treatment with a blocking anti–mouse p40 mAb in p55−/− mice from the day of immunization to day 14 after immunization partially or completely abrogated both the increase in IL-17 and IFNγ production and the expansion of CD4+IL-17+ and CD4+IFNγ+ cells (Fig. 4). These findings strongly suggest that at least one of the mechanisms by which TNFα influences the development and/or survival of Th1 and Th17 cells is by inhibition of IL-12/IL-23 p40 expression, although other mechanisms may also be involved.

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