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Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 deficiency.

Martin P, Talabot-Ayer D, Seemayer CA, Vigne S, Lamacchia C, Rodriguez E, Finckh A, Smith DE, Gabay C, Palmer G - Arthritis Res. Ther. (2013)

Bottom Line: Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor.Disease severity was monitored by clinical and histological scoring.This observation might relate to IL-33 independent effects of ST2, and/or reveal the existence of confounding variables affecting the severity of joint inflammation in these KO strains.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous work suggested implication of the IL-33/ST2 axis in the pathogenesis of human and mouse arthritis. Here, we directly investigated the role of endogenous IL-33 in K/BxN serum transfer-induced arthritis by using IL-33 knockout (KO) mice.

Methods: Arthritis was induced by injection of complete K/BxN serum or purified IgG. Disease severity was monitored by clinical and histological scoring.

Results: K/BxN serum transfer induced pronounced arthritis with similar incidence and severity in IL-33 KO and wild-type (WT) mice. In contrast, disease development was significantly reduced in ST2 KO mice. IL-33 expression in synovial tissue was comparable in arthritic WT and ST2 KO mice, and absent in IL-33 KO mice. Transfer of purified arthritogenic IgG instead of complete K/BxN serum also resulted in similar arthritis severity in IL-33 KO and WT mice, excluding a contribution of IL-33 contained in the serum of donor mice to explain this result. We investigated additional potential confounding factors, including purity of genetic background, but the mechanisms underlying reduced arthritis in ST2 KO mice remained unclear.

Conclusions: The data obtained with IL-33 KO mice indicate that endogenous IL-33 is not required for the development of joint inflammation in K/BxN serum transfer-induced arthritis. On the contrary, arthritis severity was reduced in ST2 KO mice. This observation might relate to IL-33 independent effects of ST2, and/or reveal the existence of confounding variables affecting the severity of joint inflammation in these KO strains.

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Inhibition of ST2, respectively IL-1R signaling with blocking antibody. (A, C) Incidence and (B, D) severity of K/BxN serum transfer-induced arthritis are shown for WT C57BL/6 mice treated with blocking anti-ST2 antibody (n = 10, black line), blocking anti-IL-1R1 antibody (n = 10, gray dashed line) or isotype control antibody (n = 10, black dashed line) in two independent experiments (A, B: experiment 1; C, D: experiment 2). Incidence of arthritis was markedly reduced (A, P < 0.01; C, P < 0.001, longitudinal model for binomial data) in anti-IL-1R1-treated, as compared to anti-ST2 or isotype control antibody-treated mice. (B, D) Arthritis severity scores are shown as the mean ± SEM for each group of mice. The evolution of arthritis severity scores (B, P < 0.001; D, P < 0.001, mixed model for repeated measures) and disease severity at the end of the experiment were significantly reduced in anti-IL-1R1 antibody-treated, as compared to anti-ST2 or isotype control antibody-treated mice (*P < 0.01 anti-IL-1R1 vs. isotype-control; &P < 0.01 anti-IL-1R1 vs. anti-ST2). Incidence and severity of arthritis were similar in anti-ST2 and isotype control antibody-treated mice in both experiments. WT, wild-type.
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Figure 4: Inhibition of ST2, respectively IL-1R signaling with blocking antibody. (A, C) Incidence and (B, D) severity of K/BxN serum transfer-induced arthritis are shown for WT C57BL/6 mice treated with blocking anti-ST2 antibody (n = 10, black line), blocking anti-IL-1R1 antibody (n = 10, gray dashed line) or isotype control antibody (n = 10, black dashed line) in two independent experiments (A, B: experiment 1; C, D: experiment 2). Incidence of arthritis was markedly reduced (A, P < 0.01; C, P < 0.001, longitudinal model for binomial data) in anti-IL-1R1-treated, as compared to anti-ST2 or isotype control antibody-treated mice. (B, D) Arthritis severity scores are shown as the mean ± SEM for each group of mice. The evolution of arthritis severity scores (B, P < 0.001; D, P < 0.001, mixed model for repeated measures) and disease severity at the end of the experiment were significantly reduced in anti-IL-1R1 antibody-treated, as compared to anti-ST2 or isotype control antibody-treated mice (*P < 0.01 anti-IL-1R1 vs. isotype-control; &P < 0.01 anti-IL-1R1 vs. anti-ST2). Incidence and severity of arthritis were similar in anti-ST2 and isotype control antibody-treated mice in both experiments. WT, wild-type.

Mentions: In an attempt to determine whether reduced arthritis severity in ST2 KO mice might relate to a true IL-33 independent effect of ST2 rather than to the existence of confounding variables unrelated to ST2, we used a blocking anti-ST2 antibody [24,28] to inhibit ST2 signaling during K/BxN serum transfer-induced arthritis (Figure 4). Treatment of the mice with the anti-ST2 antibody before and during development of arthritis did not reduce disease severity in two independent experiments, while blocking of the type 1 IL-1R with an isotype-matched anti-IL-1R1 blocking antibody essentially abrogated disease (Figure 4A-D). Histological severity scores confirmed clinical severity data (data not shown).


Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 deficiency.

Martin P, Talabot-Ayer D, Seemayer CA, Vigne S, Lamacchia C, Rodriguez E, Finckh A, Smith DE, Gabay C, Palmer G - Arthritis Res. Ther. (2013)

Inhibition of ST2, respectively IL-1R signaling with blocking antibody. (A, C) Incidence and (B, D) severity of K/BxN serum transfer-induced arthritis are shown for WT C57BL/6 mice treated with blocking anti-ST2 antibody (n = 10, black line), blocking anti-IL-1R1 antibody (n = 10, gray dashed line) or isotype control antibody (n = 10, black dashed line) in two independent experiments (A, B: experiment 1; C, D: experiment 2). Incidence of arthritis was markedly reduced (A, P < 0.01; C, P < 0.001, longitudinal model for binomial data) in anti-IL-1R1-treated, as compared to anti-ST2 or isotype control antibody-treated mice. (B, D) Arthritis severity scores are shown as the mean ± SEM for each group of mice. The evolution of arthritis severity scores (B, P < 0.001; D, P < 0.001, mixed model for repeated measures) and disease severity at the end of the experiment were significantly reduced in anti-IL-1R1 antibody-treated, as compared to anti-ST2 or isotype control antibody-treated mice (*P < 0.01 anti-IL-1R1 vs. isotype-control; &P < 0.01 anti-IL-1R1 vs. anti-ST2). Incidence and severity of arthritis were similar in anti-ST2 and isotype control antibody-treated mice in both experiments. WT, wild-type.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672723&req=5

Figure 4: Inhibition of ST2, respectively IL-1R signaling with blocking antibody. (A, C) Incidence and (B, D) severity of K/BxN serum transfer-induced arthritis are shown for WT C57BL/6 mice treated with blocking anti-ST2 antibody (n = 10, black line), blocking anti-IL-1R1 antibody (n = 10, gray dashed line) or isotype control antibody (n = 10, black dashed line) in two independent experiments (A, B: experiment 1; C, D: experiment 2). Incidence of arthritis was markedly reduced (A, P < 0.01; C, P < 0.001, longitudinal model for binomial data) in anti-IL-1R1-treated, as compared to anti-ST2 or isotype control antibody-treated mice. (B, D) Arthritis severity scores are shown as the mean ± SEM for each group of mice. The evolution of arthritis severity scores (B, P < 0.001; D, P < 0.001, mixed model for repeated measures) and disease severity at the end of the experiment were significantly reduced in anti-IL-1R1 antibody-treated, as compared to anti-ST2 or isotype control antibody-treated mice (*P < 0.01 anti-IL-1R1 vs. isotype-control; &P < 0.01 anti-IL-1R1 vs. anti-ST2). Incidence and severity of arthritis were similar in anti-ST2 and isotype control antibody-treated mice in both experiments. WT, wild-type.
Mentions: In an attempt to determine whether reduced arthritis severity in ST2 KO mice might relate to a true IL-33 independent effect of ST2 rather than to the existence of confounding variables unrelated to ST2, we used a blocking anti-ST2 antibody [24,28] to inhibit ST2 signaling during K/BxN serum transfer-induced arthritis (Figure 4). Treatment of the mice with the anti-ST2 antibody before and during development of arthritis did not reduce disease severity in two independent experiments, while blocking of the type 1 IL-1R with an isotype-matched anti-IL-1R1 blocking antibody essentially abrogated disease (Figure 4A-D). Histological severity scores confirmed clinical severity data (data not shown).

Bottom Line: Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor.Disease severity was monitored by clinical and histological scoring.This observation might relate to IL-33 independent effects of ST2, and/or reveal the existence of confounding variables affecting the severity of joint inflammation in these KO strains.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous work suggested implication of the IL-33/ST2 axis in the pathogenesis of human and mouse arthritis. Here, we directly investigated the role of endogenous IL-33 in K/BxN serum transfer-induced arthritis by using IL-33 knockout (KO) mice.

Methods: Arthritis was induced by injection of complete K/BxN serum or purified IgG. Disease severity was monitored by clinical and histological scoring.

Results: K/BxN serum transfer induced pronounced arthritis with similar incidence and severity in IL-33 KO and wild-type (WT) mice. In contrast, disease development was significantly reduced in ST2 KO mice. IL-33 expression in synovial tissue was comparable in arthritic WT and ST2 KO mice, and absent in IL-33 KO mice. Transfer of purified arthritogenic IgG instead of complete K/BxN serum also resulted in similar arthritis severity in IL-33 KO and WT mice, excluding a contribution of IL-33 contained in the serum of donor mice to explain this result. We investigated additional potential confounding factors, including purity of genetic background, but the mechanisms underlying reduced arthritis in ST2 KO mice remained unclear.

Conclusions: The data obtained with IL-33 KO mice indicate that endogenous IL-33 is not required for the development of joint inflammation in K/BxN serum transfer-induced arthritis. On the contrary, arthritis severity was reduced in ST2 KO mice. This observation might relate to IL-33 independent effects of ST2, and/or reveal the existence of confounding variables affecting the severity of joint inflammation in these KO strains.

Show MeSH
Related in: MedlinePlus