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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-1β mediates the pro-inflammatory effects of IL-22 in AIA. a mBSA-immunized mice were injected i.a. with IL-22 (1 ng) or saline and the concentrations of IL-1β were determined at 0.5, 1, 3 and 6 h after challenge. b mBSA-immunized WT or IL-22−/− mice were challenged i.a. with mBSA (30 μg) or saline and treated with a co-injection of IL-22 (0.3 ng) or vehicle. The concentrations of IL-1β were determined 3 h after challenge. c and d mBSA-immunized WT or IL-1R1−/− mice were challenged i.a. with IL-22 (1 ng per joint) or saline and articular hypernociception (c) and neutrophil migration (d) were evaluated 7 h following the challenge. Data are expressed as the means ± SEM (n = 5). *P < 0.05, compared with the saline group; #P < 0.05 compared the WT mBSA or WT IL-22 group; and &P < 0.05 compared with the IL-22−/− mBSA group. (−/−), deficient, AIA antigen-induced arthritis, i.a. intra-articular, IL interleukin, mBSA methylated bovine serum albumin, WT wild-type
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Fig6: IL-1β mediates the pro-inflammatory effects of IL-22 in AIA. a mBSA-immunized mice were injected i.a. with IL-22 (1 ng) or saline and the concentrations of IL-1β were determined at 0.5, 1, 3 and 6 h after challenge. b mBSA-immunized WT or IL-22−/− mice were challenged i.a. with mBSA (30 μg) or saline and treated with a co-injection of IL-22 (0.3 ng) or vehicle. The concentrations of IL-1β were determined 3 h after challenge. c and d mBSA-immunized WT or IL-1R1−/− mice were challenged i.a. with IL-22 (1 ng per joint) or saline and articular hypernociception (c) and neutrophil migration (d) were evaluated 7 h following the challenge. Data are expressed as the means ± SEM (n = 5). *P < 0.05, compared with the saline group; #P < 0.05 compared the WT mBSA or WT IL-22 group; and &P < 0.05 compared with the IL-22−/− mBSA group. (−/−), deficient, AIA antigen-induced arthritis, i.a. intra-articular, IL interleukin, mBSA methylated bovine serum albumin, WT wild-type

Mentions: According to the hypothesis that IL-22 participates in the joint inflammatory response during AIA through the stimulation of IL-1β production, the injection of IL-22 into the joints of mBSA-immunized mice significantly increased the levels of IL-1β in a time-dependent manner (Fig. 6a). Moreover, the injection of exogenous rmIL-22 into the joints of IL-22−/− mice reestablished the levels of IL-1β compared with the levels of WT mice during the mBSA challenge (Fig. 6b). In addition, joint hypernociception and neutrophil recruitment induced by i.a. injection of rmIL-22 were reduced in IL-1R1−/− mice (Fig. 6c and d). Taken together, these data indicate that IL-22 might have a modulatory role in the production of IL-1β during the early phase of AIA that accounts for the local inflammatory response.Fig. 6


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-1β mediates the pro-inflammatory effects of IL-22 in AIA. a mBSA-immunized mice were injected i.a. with IL-22 (1 ng) or saline and the concentrations of IL-1β were determined at 0.5, 1, 3 and 6 h after challenge. b mBSA-immunized WT or IL-22−/− mice were challenged i.a. with mBSA (30 μg) or saline and treated with a co-injection of IL-22 (0.3 ng) or vehicle. The concentrations of IL-1β were determined 3 h after challenge. c and d mBSA-immunized WT or IL-1R1−/− mice were challenged i.a. with IL-22 (1 ng per joint) or saline and articular hypernociception (c) and neutrophil migration (d) were evaluated 7 h following the challenge. Data are expressed as the means ± SEM (n = 5). *P < 0.05, compared with the saline group; #P < 0.05 compared the WT mBSA or WT IL-22 group; and &P < 0.05 compared with the IL-22−/− mBSA group. (−/−), deficient, AIA antigen-induced arthritis, i.a. intra-articular, IL interleukin, mBSA methylated bovine serum albumin, WT wild-type
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Related In: Results  -  Collection

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Fig6: IL-1β mediates the pro-inflammatory effects of IL-22 in AIA. a mBSA-immunized mice were injected i.a. with IL-22 (1 ng) or saline and the concentrations of IL-1β were determined at 0.5, 1, 3 and 6 h after challenge. b mBSA-immunized WT or IL-22−/− mice were challenged i.a. with mBSA (30 μg) or saline and treated with a co-injection of IL-22 (0.3 ng) or vehicle. The concentrations of IL-1β were determined 3 h after challenge. c and d mBSA-immunized WT or IL-1R1−/− mice were challenged i.a. with IL-22 (1 ng per joint) or saline and articular hypernociception (c) and neutrophil migration (d) were evaluated 7 h following the challenge. Data are expressed as the means ± SEM (n = 5). *P < 0.05, compared with the saline group; #P < 0.05 compared the WT mBSA or WT IL-22 group; and &P < 0.05 compared with the IL-22−/− mBSA group. (−/−), deficient, AIA antigen-induced arthritis, i.a. intra-articular, IL interleukin, mBSA methylated bovine serum albumin, WT wild-type
Mentions: According to the hypothesis that IL-22 participates in the joint inflammatory response during AIA through the stimulation of IL-1β production, the injection of IL-22 into the joints of mBSA-immunized mice significantly increased the levels of IL-1β in a time-dependent manner (Fig. 6a). Moreover, the injection of exogenous rmIL-22 into the joints of IL-22−/− mice reestablished the levels of IL-1β compared with the levels of WT mice during the mBSA challenge (Fig. 6b). In addition, joint hypernociception and neutrophil recruitment induced by i.a. injection of rmIL-22 were reduced in IL-1R1−/− mice (Fig. 6c and d). Taken together, these data indicate that IL-22 might have a modulatory role in the production of IL-1β during the early phase of AIA that accounts for the local inflammatory response.Fig. 6

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