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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

Protection by uridine does not involve altered anti-mBSA responses in AIA.Serum was collected at day 0, 14, 20 and 28 from the mBSA-sensitized mice treated systemically with multiple doses 0–100 mg/kg of uridine and at day 28 from the mBSA-sensitized mice treated locally 0–100 mg/kg with uridine and analyzed for mBSA specific total IgG using ELISA. (A) Anti-mBSA IgG serum levels in mice treated systemically with 0, 50, 100 mg/kg of uridine. (Red line-100 mg/kg n = 10, Blue line-50 mg/kg n = 7) (Black line-Control n = 7). (B) Anti-mBSA IgG serum levels in mice treated locally with 0 mg/kg (n = 6), 25 mg/kg (n = 6), 50 mg/kg (n = 7), 100 mg/kg (n = 7) of uridine. Data are expressed as median absorbance with interquartile range (450 nm). * p<0.05, ** p<0.01 (Mann–Whitney).
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pone.0141863.g003: Protection by uridine does not involve altered anti-mBSA responses in AIA.Serum was collected at day 0, 14, 20 and 28 from the mBSA-sensitized mice treated systemically with multiple doses 0–100 mg/kg of uridine and at day 28 from the mBSA-sensitized mice treated locally 0–100 mg/kg with uridine and analyzed for mBSA specific total IgG using ELISA. (A) Anti-mBSA IgG serum levels in mice treated systemically with 0, 50, 100 mg/kg of uridine. (Red line-100 mg/kg n = 10, Blue line-50 mg/kg n = 7) (Black line-Control n = 7). (B) Anti-mBSA IgG serum levels in mice treated locally with 0 mg/kg (n = 6), 25 mg/kg (n = 6), 50 mg/kg (n = 7), 100 mg/kg (n = 7) of uridine. Data are expressed as median absorbance with interquartile range (450 nm). * p<0.05, ** p<0.01 (Mann–Whitney).

Mentions: The protection, and lack of protection against arthritis conferred by local and systemic administration of uridine, respectively, prompted us to analyse the effects of systemic and local administration of uridine on anti-mBSA specific responses during AIA. First, we measured the levels of anti-mBSA IgG in serum on day 0, 7, 14, 20 and 28 in order to determine if systemic administration of uridine had any impact on the mBSA-specific humoral response. A minor, but still significant increase in anti-mBSA IgG was observed in animals treated with uridine, Mice receiving 100 mg/kg of uridine systemically had higher levels of serum anti-mBSA IgG on day 14, 20 and 28 than control animals receiving only vehicle (Fig 3A). A lower dose of uridine, 50 mg/kg, only resulted in increased serum levels of anti-mBSA IgG on day 20 compared to control mice. In contrast, we did not find any significant differences in serum levels of anti-mBSA specific IgG on day 28 in animals treated locally with uridine at the time of arthritis induction, and thus protected against arthritis, compared to controls (Fig 3B)


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)

Protection by uridine does not involve altered anti-mBSA responses in AIA.Serum was collected at day 0, 14, 20 and 28 from the mBSA-sensitized mice treated systemically with multiple doses 0–100 mg/kg of uridine and at day 28 from the mBSA-sensitized mice treated locally 0–100 mg/kg with uridine and analyzed for mBSA specific total IgG using ELISA. (A) Anti-mBSA IgG serum levels in mice treated systemically with 0, 50, 100 mg/kg of uridine. (Red line-100 mg/kg n = 10, Blue line-50 mg/kg n = 7) (Black line-Control n = 7). (B) Anti-mBSA IgG serum levels in mice treated locally with 0 mg/kg (n = 6), 25 mg/kg (n = 6), 50 mg/kg (n = 7), 100 mg/kg (n = 7) of uridine. Data are expressed as median absorbance with interquartile range (450 nm). * p<0.05, ** p<0.01 (Mann–Whitney).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4625961&req=5

pone.0141863.g003: Protection by uridine does not involve altered anti-mBSA responses in AIA.Serum was collected at day 0, 14, 20 and 28 from the mBSA-sensitized mice treated systemically with multiple doses 0–100 mg/kg of uridine and at day 28 from the mBSA-sensitized mice treated locally 0–100 mg/kg with uridine and analyzed for mBSA specific total IgG using ELISA. (A) Anti-mBSA IgG serum levels in mice treated systemically with 0, 50, 100 mg/kg of uridine. (Red line-100 mg/kg n = 10, Blue line-50 mg/kg n = 7) (Black line-Control n = 7). (B) Anti-mBSA IgG serum levels in mice treated locally with 0 mg/kg (n = 6), 25 mg/kg (n = 6), 50 mg/kg (n = 7), 100 mg/kg (n = 7) of uridine. Data are expressed as median absorbance with interquartile range (450 nm). * p<0.05, ** p<0.01 (Mann–Whitney).
Mentions: The protection, and lack of protection against arthritis conferred by local and systemic administration of uridine, respectively, prompted us to analyse the effects of systemic and local administration of uridine on anti-mBSA specific responses during AIA. First, we measured the levels of anti-mBSA IgG in serum on day 0, 7, 14, 20 and 28 in order to determine if systemic administration of uridine had any impact on the mBSA-specific humoral response. A minor, but still significant increase in anti-mBSA IgG was observed in animals treated with uridine, Mice receiving 100 mg/kg of uridine systemically had higher levels of serum anti-mBSA IgG on day 14, 20 and 28 than control animals receiving only vehicle (Fig 3A). A lower dose of uridine, 50 mg/kg, only resulted in increased serum levels of anti-mBSA IgG on day 20 compared to control mice. In contrast, we did not find any significant differences in serum levels of anti-mBSA specific IgG on day 28 in animals treated locally with uridine at the time of arthritis induction, and thus protected against arthritis, compared to controls (Fig 3B)

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