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Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis.

Chenna Narendra S, Chalise JP, Magnusson M, Uppugunduri S - PLoS ONE (2015)

Bottom Line: In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis.Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis.The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation.

View Article: PubMed Central - PubMed

Affiliation: Autoimmunity & Immune Regulation (AIR), Department of Clinical & Experimental Medicine, Linköping University, Linköping, Sweden.

ABSTRACT

Objective: Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis.

Methods: Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice pre-immunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint.

Results: Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium.

Conclusion: Local, but not systemic administration of uridine efficiently prevented development of antigen-induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.

No MeSH data available.


Related in: MedlinePlus

Local administration of uridine supressed synovial expression of ICAM-1 and CD18.Single dose of 0, 25, 50 and 100 mg/kg of uridine was co-administered locally along with 30 μg mBSA (intra-articularly) in right knee joint in pre-sensitized mice on day 21. At day 28, mice were sacrificed and knee joints were isolated and prepared for immunohistochemistry staining and evaluation. (A) Representative Immunohistochemistry images of non-treated and treated groups for ICAM-1 and CD18 expression. (B) Immunohistochemistry scoring of non-treated and treated groups for ICAM-1 and CD18 expression (median with interquartile range). 0 mg/kg (n = 6), 25 mg/kg (n = 6), 100 mg/kg (n = 12) of uridine. * p<0.05, ** p<0.01, *** p<0.001 (Mann–Whitney).
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pone.0141863.g007: Local administration of uridine supressed synovial expression of ICAM-1 and CD18.Single dose of 0, 25, 50 and 100 mg/kg of uridine was co-administered locally along with 30 μg mBSA (intra-articularly) in right knee joint in pre-sensitized mice on day 21. At day 28, mice were sacrificed and knee joints were isolated and prepared for immunohistochemistry staining and evaluation. (A) Representative Immunohistochemistry images of non-treated and treated groups for ICAM-1 and CD18 expression. (B) Immunohistochemistry scoring of non-treated and treated groups for ICAM-1 and CD18 expression (median with interquartile range). 0 mg/kg (n = 6), 25 mg/kg (n = 6), 100 mg/kg (n = 12) of uridine. * p<0.05, ** p<0.01, *** p<0.001 (Mann–Whitney).

Mentions: Recruitment of leukocytes to the site of injury is one of the early events in inflammation. This involves expression and activation of various cell and endothelial adhesion molecules. Supressed synovial cell influx in uridine treated joint motivated us to investigate the effects of local administration of uridine on synovial ICAM-1 and CD18. There was a significant suppression of ICAM-1 and CD18 in uridine treated mice than the controls. In mice receiving 100mg/kg of uridine, there was a 85% and 73% reduction of synovial expression of ICAM-1 and CD18 respectively (Fig 7A and 7B). A lower but significant reduction of ICAM-1 (67%) and CD18 (50%) expression was noticed with 25 mg/kg of uridine (Fig 7A and 7B).


Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis.

Chenna Narendra S, Chalise JP, Magnusson M, Uppugunduri S - PLoS ONE (2015)

Local administration of uridine supressed synovial expression of ICAM-1 and CD18.Single dose of 0, 25, 50 and 100 mg/kg of uridine was co-administered locally along with 30 μg mBSA (intra-articularly) in right knee joint in pre-sensitized mice on day 21. At day 28, mice were sacrificed and knee joints were isolated and prepared for immunohistochemistry staining and evaluation. (A) Representative Immunohistochemistry images of non-treated and treated groups for ICAM-1 and CD18 expression. (B) Immunohistochemistry scoring of non-treated and treated groups for ICAM-1 and CD18 expression (median with interquartile range). 0 mg/kg (n = 6), 25 mg/kg (n = 6), 100 mg/kg (n = 12) of uridine. * p<0.05, ** p<0.01, *** p<0.001 (Mann–Whitney).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4625961&req=5

pone.0141863.g007: Local administration of uridine supressed synovial expression of ICAM-1 and CD18.Single dose of 0, 25, 50 and 100 mg/kg of uridine was co-administered locally along with 30 μg mBSA (intra-articularly) in right knee joint in pre-sensitized mice on day 21. At day 28, mice were sacrificed and knee joints were isolated and prepared for immunohistochemistry staining and evaluation. (A) Representative Immunohistochemistry images of non-treated and treated groups for ICAM-1 and CD18 expression. (B) Immunohistochemistry scoring of non-treated and treated groups for ICAM-1 and CD18 expression (median with interquartile range). 0 mg/kg (n = 6), 25 mg/kg (n = 6), 100 mg/kg (n = 12) of uridine. * p<0.05, ** p<0.01, *** p<0.001 (Mann–Whitney).
Mentions: Recruitment of leukocytes to the site of injury is one of the early events in inflammation. This involves expression and activation of various cell and endothelial adhesion molecules. Supressed synovial cell influx in uridine treated joint motivated us to investigate the effects of local administration of uridine on synovial ICAM-1 and CD18. There was a significant suppression of ICAM-1 and CD18 in uridine treated mice than the controls. In mice receiving 100mg/kg of uridine, there was a 85% and 73% reduction of synovial expression of ICAM-1 and CD18 respectively (Fig 7A and 7B). A lower but significant reduction of ICAM-1 (67%) and CD18 (50%) expression was noticed with 25 mg/kg of uridine (Fig 7A and 7B).

Bottom Line: In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis.Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis.The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation.

View Article: PubMed Central - PubMed

Affiliation: Autoimmunity & Immune Regulation (AIR), Department of Clinical & Experimental Medicine, Linköping University, Linköping, Sweden.

ABSTRACT

Objective: Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis.

Methods: Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice pre-immunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint.

Results: Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium.

Conclusion: Local, but not systemic administration of uridine efficiently prevented development of antigen-induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.

No MeSH data available.


Related in: MedlinePlus