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Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K - Sci Rep (2015)

Bottom Line: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA).Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility.Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

ABSTRACT
Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a glucose-6-phosphate isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naïve CD4(+) T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.

No MeSH data available.


Related in: MedlinePlus

(A) Serum IL-6 concentrations in Padi4 KO mice 7 and 14 days after the GPI immunization. Serum IL-6 concentrations were measured by an enzyme-linked immunosorbent assay (WT n = 6, Padi4 KO n = 7). Gray dots; WT, open dots; Padi4 KO. Comparisons were performed using two-way analysis of variance followed by Bonferroni post-hoc test. *p < 0.05. (B) IL-6 gene expression levels in spleens were measured by quantitative PCR 7 days after the immunization (WT n = 3, Padi4 KO n = 3). Gray bars; WT, open bars; Padi4 KO.
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f5: (A) Serum IL-6 concentrations in Padi4 KO mice 7 and 14 days after the GPI immunization. Serum IL-6 concentrations were measured by an enzyme-linked immunosorbent assay (WT n = 6, Padi4 KO n = 7). Gray dots; WT, open dots; Padi4 KO. Comparisons were performed using two-way analysis of variance followed by Bonferroni post-hoc test. *p < 0.05. (B) IL-6 gene expression levels in spleens were measured by quantitative PCR 7 days after the immunization (WT n = 3, Padi4 KO n = 3). Gray bars; WT, open bars; Padi4 KO.

Mentions: IL-6 is a key cytokine in the induction of Th17 cells, and is also important for joint inflammation. Serum IL-6 concentrations were already reduced in Padi4 KO mice in the pre-arthritic phase, and the evident reduction continued in the arthritic phase (Fig. 5A). A previous study reported that myeloid lineage cells were the main source of IL-6 in a GIA model19. Although we investigated the expression of IL-6 in the spleen in the pre-arthritic phase, a significant decrease was not observed in PADI4 KO mice (Fig. 5B).


Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K - Sci Rep (2015)

(A) Serum IL-6 concentrations in Padi4 KO mice 7 and 14 days after the GPI immunization. Serum IL-6 concentrations were measured by an enzyme-linked immunosorbent assay (WT n = 6, Padi4 KO n = 7). Gray dots; WT, open dots; Padi4 KO. Comparisons were performed using two-way analysis of variance followed by Bonferroni post-hoc test. *p < 0.05. (B) IL-6 gene expression levels in spleens were measured by quantitative PCR 7 days after the immunization (WT n = 3, Padi4 KO n = 3). Gray bars; WT, open bars; Padi4 KO.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544002&req=5

f5: (A) Serum IL-6 concentrations in Padi4 KO mice 7 and 14 days after the GPI immunization. Serum IL-6 concentrations were measured by an enzyme-linked immunosorbent assay (WT n = 6, Padi4 KO n = 7). Gray dots; WT, open dots; Padi4 KO. Comparisons were performed using two-way analysis of variance followed by Bonferroni post-hoc test. *p < 0.05. (B) IL-6 gene expression levels in spleens were measured by quantitative PCR 7 days after the immunization (WT n = 3, Padi4 KO n = 3). Gray bars; WT, open bars; Padi4 KO.
Mentions: IL-6 is a key cytokine in the induction of Th17 cells, and is also important for joint inflammation. Serum IL-6 concentrations were already reduced in Padi4 KO mice in the pre-arthritic phase, and the evident reduction continued in the arthritic phase (Fig. 5A). A previous study reported that myeloid lineage cells were the main source of IL-6 in a GIA model19. Although we investigated the expression of IL-6 in the spleen in the pre-arthritic phase, a significant decrease was not observed in PADI4 KO mice (Fig. 5B).

Bottom Line: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA).Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility.Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

ABSTRACT
Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a glucose-6-phosphate isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naïve CD4(+) T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.

No MeSH data available.


Related in: MedlinePlus