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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

IL-22 differentially regulates local pro-inflammatory cytokines and chemokines in the early phase of AIA. The concentrations of IL-1β (a), IL-17 (b), MCP-1/CCL2 (c) and KC/CXCL1 (d) in the knee joint injected with mBSA (30 μg) or saline in WT and IL-22−/− mBSA-immunized mice were determined at 3 h after challenge. The levels of cytokines and chemokines were evaluated by ELISA. Data are the means ± SEM (n = 5). *P < 0.05, compared with the saline group; and #P < 0.05, compared with the 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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Fig4: IL-22 differentially regulates local pro-inflammatory cytokines and chemokines in the early phase of AIA. The concentrations of IL-1β (a), IL-17 (b), MCP-1/CCL2 (c) and KC/CXCL1 (d) in the knee joint injected with mBSA (30 μg) or saline in WT and IL-22−/− mBSA-immunized mice were determined at 3 h after challenge. The levels of cytokines and chemokines were evaluated by ELISA. Data are the means ± SEM (n = 5). *P < 0.05, compared with the saline group; and #P < 0.05, compared with the 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 identify the possible underlying mechanisms by which IL-22 mediates the local inflammatory response during AIA, local cytokine and chemokine production was determined in the joints of IL-22−/− mice. The injection of mBSA into the joints in WT immunized mice increased the local production of IL-1β, IL-17, MCP-1/CCL2, and KC/CXCL1 at 3 h after the challenge (Fig. 4a–d, respectively). Interestingly, the production of IL-1β (Fig. 4a) was reduced in IL-22−/− mice during the early phase of AIA, whereas the production of IL-17, MCP-1/CCL2 and KC/CXCL1 did not differ from WT mice (Fig. 4b–d).Fig. 4


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)

IL-22 differentially regulates local pro-inflammatory cytokines and chemokines in the early phase of AIA. The concentrations of IL-1β (a), IL-17 (b), MCP-1/CCL2 (c) and KC/CXCL1 (d) in the knee joint injected with mBSA (30 μg) or saline in WT and IL-22−/− mBSA-immunized mice were determined at 3 h after challenge. The levels of cytokines and chemokines were evaluated by ELISA. Data are the means ± SEM (n = 5). *P < 0.05, compared with the saline group; and #P < 0.05, compared with the 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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Fig4: IL-22 differentially regulates local pro-inflammatory cytokines and chemokines in the early phase of AIA. The concentrations of IL-1β (a), IL-17 (b), MCP-1/CCL2 (c) and KC/CXCL1 (d) in the knee joint injected with mBSA (30 μg) or saline in WT and IL-22−/− mBSA-immunized mice were determined at 3 h after challenge. The levels of cytokines and chemokines were evaluated by ELISA. Data are the means ± SEM (n = 5). *P < 0.05, compared with the saline group; and #P < 0.05, compared with the 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 identify the possible underlying mechanisms by which IL-22 mediates the local inflammatory response during AIA, local cytokine and chemokine production was determined in the joints of IL-22−/− mice. The injection of mBSA into the joints in WT immunized mice increased the local production of IL-1β, IL-17, MCP-1/CCL2, and KC/CXCL1 at 3 h after the challenge (Fig. 4a–d, respectively). Interestingly, the production of IL-1β (Fig. 4a) was reduced in IL-22−/− mice during the early phase of AIA, whereas the production of IL-17, MCP-1/CCL2 and KC/CXCL1 did not differ from WT mice (Fig. 4b–d).Fig. 4

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