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PMID: 20028652 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

IFN-gamma regulates the requirement for IL-17 in proteoglycan-induced arthritis.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 184 ·No. 3 ·2010-02-01 ·Pages 1552-9

Doodes PD, Cao Y, Hamel KM, Wang Y, Rodeghero RL, Mikecz K, Glant TT, Iwakura Y, Finnegan A

Abstract

The contribution of the proinflammatory cytokines IFN-gamma and IL-17 to the pathogenesis of experimental arthritis is controversial. In proteoglycan (PG)-induced arthritis (PGIA), severe arthritis is dependent on the production of IFN-gamma, whereas IL-17 is dispensable. In collagen-induced arthritis and Ag-induced arthritis, although high levels of IFN-gamma are secreted, disease is exacerbated in IFN-gamma or IFN-gamma receptor-deficient mice due to the ability of IFN-gamma to suppress IL-17 expression. In the current study, we investigated the effect of IFN-gamma on the IL-17 response and its consequences in PGIA. In PG-immunized IFN-gamma(-/-) mice, despite reduction in arthritis, the PG-specific CD4(+) T cell IL-17 response was significantly increased. Elevated IL-17 contributed to development of arthritis, as disease in IFN-gamma/IL-17(-/-) was significantly reduced in comparison with either IFN-gamma(-/-) or IL-17(-/-) mice. A contribution of IFN-gamma and IL-17 to the development of arthritis was also identified in T-bet(-/-) mice. PG-specific CD4(+) T cells from T-bet(-/-) mice produced reduced IFN-gamma and elevated concentrations of IL-17. Both IFN-gamma and IL-17 contribute to arthritis, as T-bet(-/-) mice lacking IL-17 (T-bet/IL-17(-/-)) were resistant, whereas wild-type, T-bet(-/-), and IL-17(-/-) mice were susceptible to PGIA. T cell proliferation and autoantibody production did not correlate with development of disease; however, expression of cytokines and chemokines in joint tissues demonstrate that IFN-gamma and IL-17 cooperatively contribute to inflammation. These results demonstrate that both IFN-gamma and IL-17 have the potential to induce PGIA, but it is the strength of the IFN-gamma response that regulates the contribution of each of these Th effector cytokines to disease.

MeSH Terms
Animals Arthritis, Experimental/immunology,pathology,prevention & control Arthritis, Rheumatoid/immunology,pathology,prevention & control Cells, Cultured Female Humans Inflammation Mediators/antagonists & inhibitors,metabolism,physiology Interferon-gamma/antagonists & inhibitors,deficiency,physiology Interleukin-17/biosynthesis,deficiency,physiology Mice Mice, Inbred BALB C Mice, Knockout Proteoglycans/administration & dosage,immunology T-Lymphocytes, Helper-Inducer/immunology,metabolism
Chemicals
Inflammation Mediators Interleukin-17 Proteoglycans Interferon-gamma
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Doodes Paul D
Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.
Cao Yanxia
Hamel Keith M
Wang Yumei
Rodeghero Rachel L
Mikecz Katalin
Glant Tibor T
Iwakura Yoichiro
Finnegan Alison
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.0902907
Published
2010-02-01
Epub
2009-00-18
Pages
1552-9
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2846113
Subset
IM
Grants
NIAMS NIH HHS · AR 56999 · United States
NIAMS NIH HHS · AR 47652 · United States
NIAMS NIH HHS · P01 AR045652-100002 · United States
NIAMS NIH HHS · R01 AR047652 · United States
NIAMS NIH HHS · R01 AR056999-01 · United States
NIAMS NIH HHS · R01 AR056999 · United States
NIAMS NIH HHS · P01 AR045652 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.0902907 PMC Full Text View journal details
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