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Joint production of IL-22 participates in the initial phase of antigen-induced arthritis through IL-1β production.

Pinto LG, Talbot J, Peres RS, Franca RF, Ferreira SH, Ryffel B, Aves-Filho JC, Figueiredo F, Cunha TM, Cunha FQ - Arthritis Res. Ther. (2015)

Bottom Line: The IL-22 mRNA expression and protein levels in synovial tissue were increased during the onset of AIA.Moreover, IL-22-deficient mice showed reduced synovitis (inflammatory cell influx) and lower joint IL-1β levels, whereas the production of IL-17, MCP-1/CCL2, and KC/CXCL1 and the humoral immune response were similar, compared with WT mice.These results suggest that IL-22 plays a pro-inflammatory/pathogenic role in the onset of AIA through an ASC-dependent stimulation of IL-1β production.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. larifarm@gmail.com.

ABSTRACT

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by neutrophil articular infiltration, joint pain and the progressive destruction of cartilage and bone. IL-22 is a key effector molecule that plays a critical role in autoimmune diseases. However, the function of IL-22 in the pathogenesis of RA remains controversial. In this study, we investigated the role of IL-22 in the early phase of antigen-induced arthritis (AIA) in mice.

Methods: AIA was induced in C57BL/6, IL-22(-/-), ASC(-/-) and IL-1R1(-/-) immunized mice challenged intra-articularly with methylated bovine serum albumin (mBSA). Expression of IL-22 in synovial membranes was determined by RT-PCR. Articular hypernociception was evaluated using an electronic von Frey. Neutrophil recruitment and histopathological analyses were assessed in inflamed knee joint. Joint levels of inflammatory mediators and mBSA-specific IgG concentration in the serum were measured by ELISA.

Results: The IL-22 mRNA expression and protein levels in synovial tissue were increased during the onset of AIA. In addition, pharmacological inhibition (anti-IL-22 antibody) and genetic deficiency (IL-22(-/-) mice) reduced articular pain and neutrophil migration in arthritic mice. Consistent with these findings, recombinant IL-22 joint administration promoted articular inflammation per se in WT mice, restoring joint nociception and neutrophil infiltration in IL-22(-/-) mice. Moreover, IL-22-deficient mice showed reduced synovitis (inflammatory cell influx) and lower joint IL-1β levels, whereas the production of IL-17, MCP-1/CCL2, and KC/CXCL1 and the humoral immune response were similar, compared with WT mice. Corroborating these results, the exogenous administration of IL-22 into the joints induced IL-1β production in WT mice and reestablished IL-1β production in IL-22(-/-) mice challenged with mBSA. Additionally, IL-1R1(-/-) mice showed attenuated inflammatory features induced by mBSA or IL-22 challenge. Articular nociception and neutrophil migration induced by IL-22 were also reduced in ASC(-/-) mice.

Conclusions: These results suggest that IL-22 plays a pro-inflammatory/pathogenic role in the onset of AIA through an ASC-dependent stimulation of IL-1β production.

No MeSH data available.


Related in: MedlinePlus

Participation of IL-1β in the development of AIA. a The concentrations of IL-1β in the knee joint injected with either 30 μg of mBSA or saline in mBSA-immunized mice were determined at 1, 3, 5 and 7 h after challenge. b Articular hypernociception was evaluated 1–7 h after i.a. injection with either mBSA (30 μg) or saline in mBSA-immunized WT or IL-1R1−/− mice. c Neutrophil recruitment toward the articular cavity 7 h after i.a. administration of mBSA (30 μg) or saline in mBSA-immunized WT or IL-1R1−/− mice. d-f The concentrations of IL-1β (d), KC/CXCL1 (e) and MCP-1/CCL2 (f) in the knee joint injected with mBSA (30 μg) or saline in WT and IL-1R1−/− mBSA-immunized mice were determined at 3 h after challenge. Data are the means ± SEM (n = 5). *P < 0.05, compared with the saline group; and #P < 0.05, compared with the WT mBSA group. (−/−) deficient, AIA antigen-induced arthritis, ELISA enzyme-linked immunosorbent assay, IL interleukin, KC/CXCL1 keratinocyte-derived chemokine, mBSA methylated bovine serum albumin, MCP-1/CCL2 monocyte chemoattractant protein-1, WT wild-type
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Fig5: Participation of IL-1β in the development of AIA. a The concentrations of IL-1β in the knee joint injected with either 30 μg of mBSA or saline in mBSA-immunized mice were determined at 1, 3, 5 and 7 h after challenge. b Articular hypernociception was evaluated 1–7 h after i.a. injection with either mBSA (30 μg) or saline in mBSA-immunized WT or IL-1R1−/− mice. c Neutrophil recruitment toward the articular cavity 7 h after i.a. administration of mBSA (30 μg) or saline in mBSA-immunized WT or IL-1R1−/− mice. d-f The concentrations of IL-1β (d), KC/CXCL1 (e) and MCP-1/CCL2 (f) in the knee joint injected with mBSA (30 μg) or saline in WT and IL-1R1−/− mBSA-immunized mice were determined at 3 h after challenge. Data are the means ± SEM (n = 5). *P < 0.05, compared with the saline group; and #P < 0.05, compared with the WT mBSA group. (−/−) deficient, AIA antigen-induced arthritis, ELISA enzyme-linked immunosorbent assay, IL interleukin, KC/CXCL1 keratinocyte-derived chemokine, mBSA methylated bovine serum albumin, MCP-1/CCL2 monocyte chemoattractant protein-1, WT wild-type

Mentions: To confirm the participation of IL-1β in the inflammatory response during the early phase of AIA, IL-1R1−/− mice were immunized, followed by i.a. injections of mBSA. First, mBSA challenge into the femur-tibial joint of WT mice produced a time-dependent increase in the levels of IL-1β in the joint tissues (Fig. 5a). Additionally, joint nociception and neutrophil migration during AIA were significantly diminished in IL-1R1−/− mice after mBSA challenge compared with WT mice (Fig. 5b and c). The local production of IL-1β, KC/CXCL and MCP-1/CCL2, which were induced by i.a. administration of mBSA in WT immunized mice, was not altered in IL-1R1−/− mice (Fig. 5d–f).Fig. 5


Joint production of IL-22 participates in the initial phase of antigen-induced arthritis through IL-1β production.

Pinto LG, Talbot J, Peres RS, Franca RF, Ferreira SH, Ryffel B, Aves-Filho JC, Figueiredo F, Cunha TM, Cunha FQ - Arthritis Res. Ther. (2015)

Participation of IL-1β in the development of AIA. a The concentrations of IL-1β in the knee joint injected with either 30 μg of mBSA or saline in mBSA-immunized mice were determined at 1, 3, 5 and 7 h after challenge. b Articular hypernociception was evaluated 1–7 h after i.a. injection with either mBSA (30 μg) or saline in mBSA-immunized WT or IL-1R1−/− mice. c Neutrophil recruitment toward the articular cavity 7 h after i.a. administration of mBSA (30 μg) or saline in mBSA-immunized WT or IL-1R1−/− mice. d-f The concentrations of IL-1β (d), KC/CXCL1 (e) and MCP-1/CCL2 (f) in the knee joint injected with mBSA (30 μg) or saline in WT and IL-1R1−/− mBSA-immunized mice were determined at 3 h after challenge. Data are the means ± SEM (n = 5). *P < 0.05, compared with the saline group; and #P < 0.05, compared with the WT mBSA group. (−/−) deficient, AIA antigen-induced arthritis, ELISA enzyme-linked immunosorbent assay, IL interleukin, KC/CXCL1 keratinocyte-derived chemokine, mBSA methylated bovine serum albumin, MCP-1/CCL2 monocyte chemoattractant protein-1, WT wild-type
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Fig5: Participation of IL-1β in the development of AIA. a The concentrations of IL-1β in the knee joint injected with either 30 μg of mBSA or saline in mBSA-immunized mice were determined at 1, 3, 5 and 7 h after challenge. b Articular hypernociception was evaluated 1–7 h after i.a. injection with either mBSA (30 μg) or saline in mBSA-immunized WT or IL-1R1−/− mice. c Neutrophil recruitment toward the articular cavity 7 h after i.a. administration of mBSA (30 μg) or saline in mBSA-immunized WT or IL-1R1−/− mice. d-f The concentrations of IL-1β (d), KC/CXCL1 (e) and MCP-1/CCL2 (f) in the knee joint injected with mBSA (30 μg) or saline in WT and IL-1R1−/− mBSA-immunized mice were determined at 3 h after challenge. Data are the means ± SEM (n = 5). *P < 0.05, compared with the saline group; and #P < 0.05, compared with the WT mBSA group. (−/−) deficient, AIA antigen-induced arthritis, ELISA enzyme-linked immunosorbent assay, IL interleukin, KC/CXCL1 keratinocyte-derived chemokine, mBSA methylated bovine serum albumin, MCP-1/CCL2 monocyte chemoattractant protein-1, WT wild-type
Mentions: To confirm the participation of IL-1β in the inflammatory response during the early phase of AIA, IL-1R1−/− mice were immunized, followed by i.a. injections of mBSA. First, mBSA challenge into the femur-tibial joint of WT mice produced a time-dependent increase in the levels of IL-1β in the joint tissues (Fig. 5a). Additionally, joint nociception and neutrophil migration during AIA were significantly diminished in IL-1R1−/− mice after mBSA challenge compared with WT mice (Fig. 5b and c). The local production of IL-1β, KC/CXCL and MCP-1/CCL2, which were induced by i.a. administration of mBSA in WT immunized mice, was not altered in IL-1R1−/− mice (Fig. 5d–f).Fig. 5

Bottom Line: The IL-22 mRNA expression and protein levels in synovial tissue were increased during the onset of AIA.Moreover, IL-22-deficient mice showed reduced synovitis (inflammatory cell influx) and lower joint IL-1β levels, whereas the production of IL-17, MCP-1/CCL2, and KC/CXCL1 and the humoral immune response were similar, compared with WT mice.These results suggest that IL-22 plays a pro-inflammatory/pathogenic role in the onset of AIA through an ASC-dependent stimulation of IL-1β production.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. larifarm@gmail.com.

ABSTRACT

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by neutrophil articular infiltration, joint pain and the progressive destruction of cartilage and bone. IL-22 is a key effector molecule that plays a critical role in autoimmune diseases. However, the function of IL-22 in the pathogenesis of RA remains controversial. In this study, we investigated the role of IL-22 in the early phase of antigen-induced arthritis (AIA) in mice.

Methods: AIA was induced in C57BL/6, IL-22(-/-), ASC(-/-) and IL-1R1(-/-) immunized mice challenged intra-articularly with methylated bovine serum albumin (mBSA). Expression of IL-22 in synovial membranes was determined by RT-PCR. Articular hypernociception was evaluated using an electronic von Frey. Neutrophil recruitment and histopathological analyses were assessed in inflamed knee joint. Joint levels of inflammatory mediators and mBSA-specific IgG concentration in the serum were measured by ELISA.

Results: The IL-22 mRNA expression and protein levels in synovial tissue were increased during the onset of AIA. In addition, pharmacological inhibition (anti-IL-22 antibody) and genetic deficiency (IL-22(-/-) mice) reduced articular pain and neutrophil migration in arthritic mice. Consistent with these findings, recombinant IL-22 joint administration promoted articular inflammation per se in WT mice, restoring joint nociception and neutrophil infiltration in IL-22(-/-) mice. Moreover, IL-22-deficient mice showed reduced synovitis (inflammatory cell influx) and lower joint IL-1β levels, whereas the production of IL-17, MCP-1/CCL2, and KC/CXCL1 and the humoral immune response were similar, compared with WT mice. Corroborating these results, the exogenous administration of IL-22 into the joints induced IL-1β production in WT mice and reestablished IL-1β production in IL-22(-/-) mice challenged with mBSA. Additionally, IL-1R1(-/-) mice showed attenuated inflammatory features induced by mBSA or IL-22 challenge. Articular nociception and neutrophil migration induced by IL-22 were also reduced in ASC(-/-) mice.

Conclusions: These results suggest that IL-22 plays a pro-inflammatory/pathogenic role in the onset of AIA through an ASC-dependent stimulation of IL-1β production.

No MeSH data available.


Related in: MedlinePlus