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Increased serum TWEAK levels in Psoriatic arthritis: Relationship with disease activity and matrix metalloproteinase-3 serum levels
Cytokine 53 (2011) 289–291
Contents lists available at ScienceDirect
Cytokine journal homepage: www.elsevier.com/locate/issn/10434666
Short Communication
Increased serum TWEAK levels in Psoriatic arthritis: Relationship with disease activity and matrix metalloproteinase-3 serum levels Liping Xia, Hui Shen, Weiguo Xiao, Jing Lu ⇑ First Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang 110001, China
a r t i c l e
i n f o
Article history: Received 18 June 2010 Accepted 2 December 2010 Available online 28 December 2010 Keywords: Tumor necrosis factor-related weak inducer of apoptosis Psoriatic arthritis
a b s t r a c t Objectives: We measured serum levels of Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), interleukin 15 (IL-15), monocyte chemoattractant protein 1 (MCP-1), and matrix metalloproteinase (MMP)-3 for patients with Psoriatic arthritis (PsA), and investigated whether TWEAK levels are associated with clinical disease activity and expression of proinflammatory cytokines. Methods: Forty five patients with PsA and forty five patients with osteoarthritis (OA) were involved in this study between January 2008 and December 2009. At the time of blood sample collection, the disease activity of patients with PsA was assessed according to the 28-joint count Disease Activity Score (DAS28). Serum levels of TWEAK, IL-15, MCP-1, and MMP-3 were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturers’ protocol. Results: In patients with PsA, serum TWEAK, IL-15, MCP-1 and MMP-3 levels were significantly elevated, and serum TWEAK levels showed a significant correlation with DAS28 (r = 0.405, p = 0.006) and serum MMP-3 levels (r = 0.375, p = 0.011). Conclusions: Serum TWEAK levels positively correlate with disease activity of PsA and confirm that TWEAK plays a crucial role in the pathogenesis of PsA. TWEAK may be a new important target for therapy in PsA. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that has been shown to have multiple biological activities, including stimulation of cell growth, induction of inflammatory cytokines, and stimulation of apoptosis [1]. Recent studies have suggested that TWEAK may play a crucial role in the inflammatory arthritis [2–4]. Psoriatic arthritis (PsA) is a chronic and heterogeneous inflammatory joint disease that involves synovial tissue, enthesitis and skin, and that may result in significant joint damage [5]. van Kuijk et al. [4] showed that TWEAK and pro-inflammatory cytokines [6,7], including interleukin 1 (IL-1), IL-6, IL-15, and IL-18, were abundantly expressed in the inflamed synovium of patients with PsA, where they may promote synovial inflammation and joint destruction. Of importance, there is persistent expression of TWEAK after TNF blockade, suggesting that TWEAK may be a new important therapeutic targets in PsA [4]. However, serum TWEAK concentrations in patients with PsA have not been reported, and the association of TWEAK with disease activity or proinflammatory cytokine expression has not been ⇑ Corresponding author. Tel.: +86 024 83282549. E-mail addresses: [email protected] (L.P. Xia), [email protected] (H. Shen), [email protected] (W.G. Xiao), [email protected] (J. Lu). 1043-4666/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2010.12.003
investigated. In this study, we measured serum levels of TWEAK, IL-15, monocyte chemoattractant protein 1 (MCP-1), and matrix metalloproteinase (MMP)-3 for patients with PSA, and investigated whether TWEAK levels are associated with clinical disease activity and expression of proinflammatory cytokines.
2. Materials and methods 2.1. Patients Forty five patients (19 women and 26 men; mean age 42.9 ± 13.6 years; mean disease duration 3.9 ± 2.7 years) with PsA and forty five patients (18 women and 27 men; mean age 55.6 ± 10.3 years; mean disease duration 6.6 ± 6.3 years) with ostarthritis (OA) were involved in this study between January 2008 and December 2009. All patients with PsA fulfilled the CASPAR (ClASsification of Psoriatic ARthritis) group criteria [8]. Control blood samples were obtained from 45 healthy blood donors with no evidence of connective tissue disease (20 women and 25 men; mean age 46.6 ± 13.4 years). At the time of blood sample collection, the disease activity of patients with PsA was assessed according to the 28-joint count Disease Activity Score (DAS28) using the number of swollen and tender joints, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).
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L.P. Xia et al. / Cytokine 53 (2011) 289–291
Informed consent was obtained from all patients. The procedures followed were approved by the Ethics Committee of China Medical University.
2.2. Measurements of serum levels of TWEAK, IL-15, MCP-1, and MMP-3 Serum samples were collected and stored at 80 °C until assayed. Serum levels of TWEAK, IL-15, MCP-1, and MMP-3 were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturers’ protocol. ELISA kits for human TWEAK and IL-15 were purchased from Bender Medsystems, Vienna, Austria, and kits for human MCP-1 and MMP-3 were from R and D Systems Inc., Minneapolis, MN, USA.
2.3. Statistical analysis All statistical analyses were performed using SPSS version 13.0 and results (mean ± standard deviation) of biochemical assays represent duplicate measurements. Groups were compared using the Mann–Whitney nonparametric U-test or independent t-test as appropriate. Spearman’s rank correlation coefficient was used to test the correlation between serum TWEAK and DAS28 or cytokine levels. The p-values less than 0.05 were considered statistically significant.
Fig. 1B. Serum IL-15 levels in patients with PsA were significantly higher than those in patients with OA and controls.
3. Results 3.1. Serum TWEAK and cytokine concentrations Serum TWEAK levels were significantly higher in patients with PsA (75.1 ± 41.0 pg/ml) than in healthy controls (34.8 ± 19.8 pg/ ml; p < 0.05) and patients with OA (47.3 ± 31.0 pg/ml; p < 0.05) (Fig. 1A). Compared with healthy controls, patients with PsA had significantly higher serum concentrations of IL-15 (430.4 ± 258.2 vs. 270.5 ± 146.8 pg/ml for controls; p < 0.05), MCP-1 (540.4 ± 285.1 vs. 344.8 ± 157.1 pg/ml; p < 0.05), and MMP-3 (65956.6 ± 28917.9 vs. 28525.7 ± 18635.4 pg/ml; p < 0.05). (Figs. 1B,C,D). There was no significant difference in serum TWEAK, IL-15, MCP-1, and MMP-3 levels between patients with OA and healthy controls.
Fig. 1C. Serum MCP-1 levels in patients with PsA were significantly higher than those in patients with OA and controls.
Fig. 1A. Serum TWEAK levels in patients with PsA were significantly higher than those in patients with OA and controls.
Fig. 1D. Serum MMP-3 levels in patients with PsA were significantly higher than those in patients with OA and controls.
L.P. Xia et al. / Cytokine 53 (2011) 289–291
3.2. Correlations of TWEAK levels with disease activity and cytokine expression We also study the correlations of serum TWEAK levels with the clinical disease activity parameter (DAS28) and proinflammatory cytokine levels. In patients with PsA, serum TWEAK levels showed a significant correlation with DAS28 (r = 0.405, p = 0.006) and serum MMP-3 levels (r = 0.375, p = 0.011), but not with serum IL-15, and MCP-1 levels. 4. Discussion In this study we have demonstrated significantly increased serum TWEAK levels in patients with PsA compared with patients with OA and healthy subjects. Moreover, our results indicate a significant correlation between serum TWEAK levels and clinical parameters reflecting disease activity in patients with PsA, suggesting a possible role for TWEAK in the pathogenesis of PsA. Recent studies [4] have shown that TWEAK and Fn14 are both abundantly expressed in the inflamed synovium of patients with PsA, where they may promote synovial inflammation and joint destruction by the production of chemokines, cytokines and MMPs, and promotion of cell proliferation and angiogenesis. Further examinations [3] also revealed a good correlation between the decreased number of infiltrating inflammatory cells and the lowered production of chemokines and cytokines due to TWEAK blockade, providing clear evidence that TWEAK may play a role in both joint inflammation and tissue damage in the context of inflammatory arthritis. Chicheportiche et al. demonstrated that TWEAK can induce the production of proteolytic enzyme MMP-1 and the proinflammatory molecules prostaglandin E2, IL-6, IL-8, and RANTES (regulated on activation normal T-cell expressed and secreted) by normal human dermal fibroblasts and synoviocytes obtained from RA patients [9]. Our study also demonstrated that the serum levels of IL-15, MCP-1, and MMP-3 were significantly increased in patients with PsA compared with patients with OA and healthy subjects. Further-
291
more, our results indicated a significant correlation between serum TWEAK levels and MMP-3 levels in patients with PsA, suggesting TWEAK may play a crucial role in the joint destruction of PsA. How TWEAK induces IL-15, MCP-1, and MMP-3 from synovial fibroblasts in patients with PsA remains to be better investigated. In summary, our results suggest that serum TWEAK levels positively correlate with disease activity and the joint destruction of PsA. Further studies are necessary to determine the implication of these correlations and to elucidate the role of TWEAK in the pathogenesis of PsA. TWEAK may be a new important target for therapy in PsA. References [1] Wiley SR, Winkles JA. TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor. Cytokine Growth Factor Rev 2003;14(3–4):241–9. [2] Kamijo S, Nakajima A, Kamata K, Kurosawa H, Yagita H, Okumura K. Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA. Rheumatology (Oxford) 2008 Apr;47(4):442–50. [3] Kamata K, Kamijo S, Nakajima A, Koyanagi A, Kurosawa H, Yagita H, et al. Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced arthritis. J Immunol 2006;177(9):6433–9. [4] van Kuijk AW, Wijbrandts CA, Vinkenoog M, Zheng TS, Reedquist KA, Tak PP. TWEAK and its receptor Fn14 in the synovium of patients with rheumatoid arthritis compared to psoriatic arthritis and its response to tumour necrosis factor blockade. Ann Rheum Dis 2010 Jan;69(1):301–4. [5] Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64(Suppl. 2ii):14–7. [6] van Kuijk AW, Reinders-Blankert P, Smeets TJ, Dijkmans BA, Tak PP. Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment. Ann Rheum Dis 2006 Dec;65(12):1551–7. [7] McLInnes IB. Cytokine targeting in psoriasis and psoriatic arthritis: beyond TNFalpha. Ernst Schering Res Found Workshop 2006;56:29–44. [8] Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006 Aug;54(8):2665–73. [9] Chicheportiche Y, Chicheportiche R, Sizing I, Thompson J, Benjamin CB, Ambrose C, et al. Proinflammatory activity of TWEAK on human dermal fibroblasts and synoviocytes: blocking and enhancing effects of anti-TWEAK monoclonal antibodies. Arthritis Res 2002;4(2):126–33.
Contents lists available at ScienceDirect
Cytokine journal homepage: www.elsevier.com/locate/issn/10434666
Short Communication
Increased serum TWEAK levels in Psoriatic arthritis: Relationship with disease activity and matrix metalloproteinase-3 serum levels Liping Xia, Hui Shen, Weiguo Xiao, Jing Lu ⇑ First Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang 110001, China
a r t i c l e
i n f o
Article history: Received 18 June 2010 Accepted 2 December 2010 Available online 28 December 2010 Keywords: Tumor necrosis factor-related weak inducer of apoptosis Psoriatic arthritis
a b s t r a c t Objectives: We measured serum levels of Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), interleukin 15 (IL-15), monocyte chemoattractant protein 1 (MCP-1), and matrix metalloproteinase (MMP)-3 for patients with Psoriatic arthritis (PsA), and investigated whether TWEAK levels are associated with clinical disease activity and expression of proinflammatory cytokines. Methods: Forty five patients with PsA and forty five patients with osteoarthritis (OA) were involved in this study between January 2008 and December 2009. At the time of blood sample collection, the disease activity of patients with PsA was assessed according to the 28-joint count Disease Activity Score (DAS28). Serum levels of TWEAK, IL-15, MCP-1, and MMP-3 were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturers’ protocol. Results: In patients with PsA, serum TWEAK, IL-15, MCP-1 and MMP-3 levels were significantly elevated, and serum TWEAK levels showed a significant correlation with DAS28 (r = 0.405, p = 0.006) and serum MMP-3 levels (r = 0.375, p = 0.011). Conclusions: Serum TWEAK levels positively correlate with disease activity of PsA and confirm that TWEAK plays a crucial role in the pathogenesis of PsA. TWEAK may be a new important target for therapy in PsA. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that has been shown to have multiple biological activities, including stimulation of cell growth, induction of inflammatory cytokines, and stimulation of apoptosis [1]. Recent studies have suggested that TWEAK may play a crucial role in the inflammatory arthritis [2–4]. Psoriatic arthritis (PsA) is a chronic and heterogeneous inflammatory joint disease that involves synovial tissue, enthesitis and skin, and that may result in significant joint damage [5]. van Kuijk et al. [4] showed that TWEAK and pro-inflammatory cytokines [6,7], including interleukin 1 (IL-1), IL-6, IL-15, and IL-18, were abundantly expressed in the inflamed synovium of patients with PsA, where they may promote synovial inflammation and joint destruction. Of importance, there is persistent expression of TWEAK after TNF blockade, suggesting that TWEAK may be a new important therapeutic targets in PsA [4]. However, serum TWEAK concentrations in patients with PsA have not been reported, and the association of TWEAK with disease activity or proinflammatory cytokine expression has not been ⇑ Corresponding author. Tel.: +86 024 83282549. E-mail addresses: [email protected] (L.P. Xia), [email protected] (H. Shen), [email protected] (W.G. Xiao), [email protected] (J. Lu). 1043-4666/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2010.12.003
investigated. In this study, we measured serum levels of TWEAK, IL-15, monocyte chemoattractant protein 1 (MCP-1), and matrix metalloproteinase (MMP)-3 for patients with PSA, and investigated whether TWEAK levels are associated with clinical disease activity and expression of proinflammatory cytokines.
2. Materials and methods 2.1. Patients Forty five patients (19 women and 26 men; mean age 42.9 ± 13.6 years; mean disease duration 3.9 ± 2.7 years) with PsA and forty five patients (18 women and 27 men; mean age 55.6 ± 10.3 years; mean disease duration 6.6 ± 6.3 years) with ostarthritis (OA) were involved in this study between January 2008 and December 2009. All patients with PsA fulfilled the CASPAR (ClASsification of Psoriatic ARthritis) group criteria [8]. Control blood samples were obtained from 45 healthy blood donors with no evidence of connective tissue disease (20 women and 25 men; mean age 46.6 ± 13.4 years). At the time of blood sample collection, the disease activity of patients with PsA was assessed according to the 28-joint count Disease Activity Score (DAS28) using the number of swollen and tender joints, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).
290
L.P. Xia et al. / Cytokine 53 (2011) 289–291
Informed consent was obtained from all patients. The procedures followed were approved by the Ethics Committee of China Medical University.
2.2. Measurements of serum levels of TWEAK, IL-15, MCP-1, and MMP-3 Serum samples were collected and stored at 80 °C until assayed. Serum levels of TWEAK, IL-15, MCP-1, and MMP-3 were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturers’ protocol. ELISA kits for human TWEAK and IL-15 were purchased from Bender Medsystems, Vienna, Austria, and kits for human MCP-1 and MMP-3 were from R and D Systems Inc., Minneapolis, MN, USA.
2.3. Statistical analysis All statistical analyses were performed using SPSS version 13.0 and results (mean ± standard deviation) of biochemical assays represent duplicate measurements. Groups were compared using the Mann–Whitney nonparametric U-test or independent t-test as appropriate. Spearman’s rank correlation coefficient was used to test the correlation between serum TWEAK and DAS28 or cytokine levels. The p-values less than 0.05 were considered statistically significant.
Fig. 1B. Serum IL-15 levels in patients with PsA were significantly higher than those in patients with OA and controls.
3. Results 3.1. Serum TWEAK and cytokine concentrations Serum TWEAK levels were significantly higher in patients with PsA (75.1 ± 41.0 pg/ml) than in healthy controls (34.8 ± 19.8 pg/ ml; p < 0.05) and patients with OA (47.3 ± 31.0 pg/ml; p < 0.05) (Fig. 1A). Compared with healthy controls, patients with PsA had significantly higher serum concentrations of IL-15 (430.4 ± 258.2 vs. 270.5 ± 146.8 pg/ml for controls; p < 0.05), MCP-1 (540.4 ± 285.1 vs. 344.8 ± 157.1 pg/ml; p < 0.05), and MMP-3 (65956.6 ± 28917.9 vs. 28525.7 ± 18635.4 pg/ml; p < 0.05). (Figs. 1B,C,D). There was no significant difference in serum TWEAK, IL-15, MCP-1, and MMP-3 levels between patients with OA and healthy controls.
Fig. 1C. Serum MCP-1 levels in patients with PsA were significantly higher than those in patients with OA and controls.
Fig. 1A. Serum TWEAK levels in patients with PsA were significantly higher than those in patients with OA and controls.
Fig. 1D. Serum MMP-3 levels in patients with PsA were significantly higher than those in patients with OA and controls.
L.P. Xia et al. / Cytokine 53 (2011) 289–291
3.2. Correlations of TWEAK levels with disease activity and cytokine expression We also study the correlations of serum TWEAK levels with the clinical disease activity parameter (DAS28) and proinflammatory cytokine levels. In patients with PsA, serum TWEAK levels showed a significant correlation with DAS28 (r = 0.405, p = 0.006) and serum MMP-3 levels (r = 0.375, p = 0.011), but not with serum IL-15, and MCP-1 levels. 4. Discussion In this study we have demonstrated significantly increased serum TWEAK levels in patients with PsA compared with patients with OA and healthy subjects. Moreover, our results indicate a significant correlation between serum TWEAK levels and clinical parameters reflecting disease activity in patients with PsA, suggesting a possible role for TWEAK in the pathogenesis of PsA. Recent studies [4] have shown that TWEAK and Fn14 are both abundantly expressed in the inflamed synovium of patients with PsA, where they may promote synovial inflammation and joint destruction by the production of chemokines, cytokines and MMPs, and promotion of cell proliferation and angiogenesis. Further examinations [3] also revealed a good correlation between the decreased number of infiltrating inflammatory cells and the lowered production of chemokines and cytokines due to TWEAK blockade, providing clear evidence that TWEAK may play a role in both joint inflammation and tissue damage in the context of inflammatory arthritis. Chicheportiche et al. demonstrated that TWEAK can induce the production of proteolytic enzyme MMP-1 and the proinflammatory molecules prostaglandin E2, IL-6, IL-8, and RANTES (regulated on activation normal T-cell expressed and secreted) by normal human dermal fibroblasts and synoviocytes obtained from RA patients [9]. Our study also demonstrated that the serum levels of IL-15, MCP-1, and MMP-3 were significantly increased in patients with PsA compared with patients with OA and healthy subjects. Further-
291
more, our results indicated a significant correlation between serum TWEAK levels and MMP-3 levels in patients with PsA, suggesting TWEAK may play a crucial role in the joint destruction of PsA. How TWEAK induces IL-15, MCP-1, and MMP-3 from synovial fibroblasts in patients with PsA remains to be better investigated. In summary, our results suggest that serum TWEAK levels positively correlate with disease activity and the joint destruction of PsA. Further studies are necessary to determine the implication of these correlations and to elucidate the role of TWEAK in the pathogenesis of PsA. TWEAK may be a new important target for therapy in PsA. References [1] Wiley SR, Winkles JA. TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor. Cytokine Growth Factor Rev 2003;14(3–4):241–9. [2] Kamijo S, Nakajima A, Kamata K, Kurosawa H, Yagita H, Okumura K. Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA. Rheumatology (Oxford) 2008 Apr;47(4):442–50. [3] Kamata K, Kamijo S, Nakajima A, Koyanagi A, Kurosawa H, Yagita H, et al. Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced arthritis. J Immunol 2006;177(9):6433–9. [4] van Kuijk AW, Wijbrandts CA, Vinkenoog M, Zheng TS, Reedquist KA, Tak PP. TWEAK and its receptor Fn14 in the synovium of patients with rheumatoid arthritis compared to psoriatic arthritis and its response to tumour necrosis factor blockade. Ann Rheum Dis 2010 Jan;69(1):301–4. [5] Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64(Suppl. 2ii):14–7. [6] van Kuijk AW, Reinders-Blankert P, Smeets TJ, Dijkmans BA, Tak PP. Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment. Ann Rheum Dis 2006 Dec;65(12):1551–7. [7] McLInnes IB. Cytokine targeting in psoriasis and psoriatic arthritis: beyond TNFalpha. Ernst Schering Res Found Workshop 2006;56:29–44. [8] Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006 Aug;54(8):2665–73. [9] Chicheportiche Y, Chicheportiche R, Sizing I, Thompson J, Benjamin CB, Ambrose C, et al. Proinflammatory activity of TWEAK on human dermal fibroblasts and synoviocytes: blocking and enhancing effects of anti-TWEAK monoclonal antibodies. Arthritis Res 2002;4(2):126–33.