Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of interferon-gamma and counteraction by interferon-gamma.
BACKGROUND
Interleukin (IL)-17 is a pro-inflammatory cytokine in rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Since interferon (IFN)-gamma inhibits Th17 cell development, IFN-gamma receptor knockout (IFN-gammaR KO) mice develop CIA more readily. We took advantage of this model to analyse the mechanisms of action of IL-17 in arthritis. The role of IFN-gamma on the effector mechanisms of IL-17 in an in vitro system was also investigated.


METHODS
IFN-gammaR KO mice induced for CIA were treated with anti-IL-17 or control antibody. The collagen type II (CII)-specific humoral and cellular autoimmune responses, myelopoiesis, osteoclastogenesis, and systemic cytokine production were determined. Mouse embryo fibroblasts (MEF) were stimulated with IL-17, tumor necrosis factor (TNF)-alpha and the expression of cytokines and chemokines were determined.


RESULTS
A preventive anti-IL-17 antibody treatment inhibited CIA in IFNgammaR KO mice. In the joints of anti-IL-17-treated mice, neutrophil influx and bone destruction were absent. Treatment reduced the cellular autoimmune response as well as the splenic expansion of CD11b+ cells, and production of myelopoietic cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-6. IL-17 and TNF-alpha synergistically induced granulocyte chemotactic protein-2 (GCP-2), IL-6 and receptor activator of NFkappaB ligand (RANKL) in MEF. This induction was profoundly inhibited by IFN-gamma in a STAT-1 (signal transducer and activator of transcription-1)-dependent way.


CONCLUSIONS
In the absence of IFN-gamma, IL-17 mediates its pro-inflammatory effects mainly through stimulatory effects on granulopoiesis, neutrophil infiltration and bone destruction. In vitro IFN-gamma profoundly inhibits the effector function of IL-17. Thus, aside from the well-known inhibition of the development of Th17 cells by IFN-gamma, this may be an additional mechanism through which IFN-gamma attenuates autoimmune diseases.
Kelchtermans
Hilde
H
Laboratories of Immunobiology, Rega Institute, Faculty of Medicine, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven, Belgium. Hilde.Kelchtermans@apitope.com
Schurgers
Evelien
E
Geboes
Lies
L
Mitera
Tania
T
Van Damme
Jo
J
Van Snick
Jacques
J
Uyttenhove
Catherine
C
Matthys
Patrick
P
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D039481:CD11b Antigen / Q000276:immunology; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000096743:Interferon gamma Receptor
D039481:CD11b Antigen; D024043:Collagen Type II; D016207:Cytokines; D007371:Interferon-gamma; D020381:Interleukin-17; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor
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