IL-33 exacerbates antigen-induced arthritis by activating mast cells

Damo Xu, Hui-Rong Jiang, Peter Kewin, Yubin Li, Rong Mu, Alasdair R Fraser, Nick Pitman, Mariola Kurowska-Stolarska, Andrew N J McKenzie, Iain B McInnes, Foo Y Liew

Research output: Contribution to journalArticle

335 Citations (Scopus)

Abstract

IL-33, a cytokine of the IL-1 family, is closely associated with type II T cell responses. Here, we report an unexpected proinflammatory role of IL-33 in inflammatory arthritis. IL-33 was expressed in synovial fibroblasts from patients with rheumatoid arthritis (RA). Expression was markedly elevated in vitro by inflammatory cytokines. Mice lacking ST2, the IL-33 receptor alpha-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFalpha, and IFNgamma), and antibody production. Conversely, treatment of wild-type (WT) but not ST2(-/-) mice with IL-33 exacerbated CIA and elevated production of both proinflammatory cytokines and anti-collagen antibodies. Mast cells expressed high levels of ST2 and responded directly to IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. In vivo, IL-33 treatment exacerbated CIA in ST2(-/-) mice engrafted with mast cells from WT but not from ST2(-/-) mice. Disease exacerbation was accompanied by elevated expression levels of proinflammatory cytokines. Our results demonstrate that IL-33 is a critical proinflammatory cytokine for inflammatory joint disease that integrates fibroblast activation with downstream immune activation mainly via an IL-33-driven, mast-cell-dependent pathway. Thus, this IL-1 superfamily member represents a therapeutic target for RA.
LanguageEnglish
Pages10913-10918
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume105
Issue number31
DOIs
Publication statusPublished - 2008

Fingerprint

Mast Cells
Arthritis
Antigens
Cytokines
Experimental Arthritis
Interleukin-1
Rheumatoid Arthritis
Collagen
Fibroblasts
Interleukin-33
Interleukin-17
Joint Diseases
Chemokines
Antibody Formation
Disease Progression
Anti-Idiotypic Antibodies
Therapeutics
Tumor Necrosis Factor-alpha
T-Lymphocytes

Keywords

  • animals
  • arthritis
  • enzyme-linked immunosorbent assay
  • flow cytometry
  • humans
  • interleukins
  • mast cells
  • membrane proteins
  • mice
  • receptors
  • synovial membrane

Cite this

Xu, Damo ; Jiang, Hui-Rong ; Kewin, Peter ; Li, Yubin ; Mu, Rong ; Fraser, Alasdair R ; Pitman, Nick ; Kurowska-Stolarska, Mariola ; McKenzie, Andrew N J ; McInnes, Iain B ; Liew, Foo Y. / IL-33 exacerbates antigen-induced arthritis by activating mast cells. In: Proceedings of the National Academy of Sciences . 2008 ; Vol. 105, No. 31. pp. 10913-10918.
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abstract = "IL-33, a cytokine of the IL-1 family, is closely associated with type II T cell responses. Here, we report an unexpected proinflammatory role of IL-33 in inflammatory arthritis. IL-33 was expressed in synovial fibroblasts from patients with rheumatoid arthritis (RA). Expression was markedly elevated in vitro by inflammatory cytokines. Mice lacking ST2, the IL-33 receptor alpha-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFalpha, and IFNgamma), and antibody production. Conversely, treatment of wild-type (WT) but not ST2(-/-) mice with IL-33 exacerbated CIA and elevated production of both proinflammatory cytokines and anti-collagen antibodies. Mast cells expressed high levels of ST2 and responded directly to IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. In vivo, IL-33 treatment exacerbated CIA in ST2(-/-) mice engrafted with mast cells from WT but not from ST2(-/-) mice. Disease exacerbation was accompanied by elevated expression levels of proinflammatory cytokines. Our results demonstrate that IL-33 is a critical proinflammatory cytokine for inflammatory joint disease that integrates fibroblast activation with downstream immune activation mainly via an IL-33-driven, mast-cell-dependent pathway. Thus, this IL-1 superfamily member represents a therapeutic target for RA.",
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author = "Damo Xu and Hui-Rong Jiang and Peter Kewin and Yubin Li and Rong Mu and Fraser, {Alasdair R} and Nick Pitman and Mariola Kurowska-Stolarska and McKenzie, {Andrew N J} and McInnes, {Iain B} and Liew, {Foo Y}",
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Xu, D, Jiang, H-R, Kewin, P, Li, Y, Mu, R, Fraser, AR, Pitman, N, Kurowska-Stolarska, M, McKenzie, ANJ, McInnes, IB & Liew, FY 2008, 'IL-33 exacerbates antigen-induced arthritis by activating mast cells' Proceedings of the National Academy of Sciences , vol. 105, no. 31, pp. 10913-10918. https://doi.org/10.1073/pnas.0801898105

IL-33 exacerbates antigen-induced arthritis by activating mast cells. / Xu, Damo; Jiang, Hui-Rong; Kewin, Peter; Li, Yubin; Mu, Rong; Fraser, Alasdair R; Pitman, Nick; Kurowska-Stolarska, Mariola; McKenzie, Andrew N J; McInnes, Iain B; Liew, Foo Y.

In: Proceedings of the National Academy of Sciences , Vol. 105, No. 31, 2008, p. 10913-10918.

Research output: Contribution to journalArticle

TY - JOUR

T1 - IL-33 exacerbates antigen-induced arthritis by activating mast cells

AU - Xu, Damo

AU - Jiang, Hui-Rong

AU - Kewin, Peter

AU - Li, Yubin

AU - Mu, Rong

AU - Fraser, Alasdair R

AU - Pitman, Nick

AU - Kurowska-Stolarska, Mariola

AU - McKenzie, Andrew N J

AU - McInnes, Iain B

AU - Liew, Foo Y

PY - 2008

Y1 - 2008

N2 - IL-33, a cytokine of the IL-1 family, is closely associated with type II T cell responses. Here, we report an unexpected proinflammatory role of IL-33 in inflammatory arthritis. IL-33 was expressed in synovial fibroblasts from patients with rheumatoid arthritis (RA). Expression was markedly elevated in vitro by inflammatory cytokines. Mice lacking ST2, the IL-33 receptor alpha-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFalpha, and IFNgamma), and antibody production. Conversely, treatment of wild-type (WT) but not ST2(-/-) mice with IL-33 exacerbated CIA and elevated production of both proinflammatory cytokines and anti-collagen antibodies. Mast cells expressed high levels of ST2 and responded directly to IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. In vivo, IL-33 treatment exacerbated CIA in ST2(-/-) mice engrafted with mast cells from WT but not from ST2(-/-) mice. Disease exacerbation was accompanied by elevated expression levels of proinflammatory cytokines. Our results demonstrate that IL-33 is a critical proinflammatory cytokine for inflammatory joint disease that integrates fibroblast activation with downstream immune activation mainly via an IL-33-driven, mast-cell-dependent pathway. Thus, this IL-1 superfamily member represents a therapeutic target for RA.

AB - IL-33, a cytokine of the IL-1 family, is closely associated with type II T cell responses. Here, we report an unexpected proinflammatory role of IL-33 in inflammatory arthritis. IL-33 was expressed in synovial fibroblasts from patients with rheumatoid arthritis (RA). Expression was markedly elevated in vitro by inflammatory cytokines. Mice lacking ST2, the IL-33 receptor alpha-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFalpha, and IFNgamma), and antibody production. Conversely, treatment of wild-type (WT) but not ST2(-/-) mice with IL-33 exacerbated CIA and elevated production of both proinflammatory cytokines and anti-collagen antibodies. Mast cells expressed high levels of ST2 and responded directly to IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. In vivo, IL-33 treatment exacerbated CIA in ST2(-/-) mice engrafted with mast cells from WT but not from ST2(-/-) mice. Disease exacerbation was accompanied by elevated expression levels of proinflammatory cytokines. Our results demonstrate that IL-33 is a critical proinflammatory cytokine for inflammatory joint disease that integrates fibroblast activation with downstream immune activation mainly via an IL-33-driven, mast-cell-dependent pathway. Thus, this IL-1 superfamily member represents a therapeutic target for RA.

KW - animals

KW - arthritis

KW - enzyme-linked immunosorbent assay

KW - flow cytometry

KW - humans

KW - interleukins

KW - mast cells

KW - membrane proteins

KW - mice

KW - receptors

KW - synovial membrane

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DO - 10.1073/pnas.0801898105

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T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

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