Antiinflammatory effects of Tacrolimus in a mouse model of pleurisy.
BACKGROUND
Tacrolimus is an antibiotic macrolide with immunosuppressant properties isolated from Streptomyces tsukubaensis.


OBJECTIVE
This study evaluated whether the acute and systemic administration of Tacrolimus significantly interfered in leukocyte migration, exudation, myeloperoxidase and adenosine-deaminase and nitric oxide levels, as well as Interleukin-1 (IL-1beta) and tumor necrosis factor alpha (TNFalpha) levels in a mouse model of pleurisy in comparison to those obtained with dexamethasone.


METHODS
Pleurisy was induced by carrageenan (Cg, 1%), bradykinin (BK, 10 nmol), histamine (HIS, 1 micromol) or substance P (PS, 20 nmol) administered by intrapleural route (ipl.) and the inflammatory parameters (cell migration and exudation) were analyzed 4 h after. In the model of pleurisy induced by carrageenan, other markers in the pleural fluid, such as cytokines (TNFalpha and Il-1beta), nitrite/nitrate (NOx), myeloperoxidase (MPO) and adenosine-deaminase (ADA) levels, were also studied. Dexamethaseone (0.5 mg/kg, i.p., 0.5 h before) was also analyzed in all protocols.


RESULTS
In the pleurisy induced by carrageenan, Tacrolimus (1 mg/kg, i.p.) and dexamethasone (0.5 mg/kg, i.p.) administered 0.5 h before caused a significant decrease in leukocytes, neutrophils and exudation (P < 0.01). Under the same conditions, Tacrolimus and dexamethasone did not modify the blood's white or red cells (P > 0.05). Tacrolimus showed a long lasting antiinflammatory effect, inhibiting leukocytes and neutrophils for up to 24 h (P < 0.01), whereas the inhibition of exudation was less marked (up to 2 h) (P < 0.01). These drugs caused a marked reduction in MPO activity, as well as IL-1beta and TNFalpha levels (P < 0.01), but only Tacrolimus inhibited ADA activity (P < 0.01). On the other hand, dexamethasone, but not Tacrolimus, inhibited NOx levels (P < 0.01). In the same conditions, Tacrolimus significantly inhibited cell migration induced by either bradykinin, histamine or substance P (P < 0.05). In a similar manner, dexamethasone inhibited leukocyte influx induced by bradykinin and histamine (P < 0.05). Regarding exudation effects, dexamethasone markedly inhibited this parameter induced by BK, HIS or SP, whereas Tacrolimus only inhibited exudation caused by HIS (P < 0.05).


CONCLUSIONS
The results of the present work indicate that Tacrolimus showed important antiinflammatory properties against pleurisy in mice that are different from those caused by dexamethasone. The inhibition of proinflammatory cytokine (TNFalpha, IL-1beta), enzyme (myeloperoxidase, adenosine-deaminase) and mediator (bradykinin, histamine, substance P) release and/or action appears to account for Tacrolimus's actions.
Pereira
Robson
R
Department of Medical Science, Universidade Federal de Santa Catarina, Campus Universitário - Trindade, 88040-970, Florianópolis, SC, Brazil.
Medeiros
Yara Santos
YS
Fröde
Tânia Silvia
TS
D000243:Adenosine Deaminase / Q000097:blood / Q000276:immunology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001920:Bradykinin / Q000494:pharmacology / Q000633:toxicity; D002351:Carrageenan / Q000494:pharmacology / Q000633:toxicity; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D006632:Histamine / Q000494:pharmacology / Q000633:toxicity; D018494:Histamine Agents / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D007375:Interleukin-1 / Q000097:blood / Q000276:immunology; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000097:blood / Q000276:immunology; D009195:Peroxidase / Q000097:blood / Q000276:immunology; D010998:Pleurisy / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D016559:Tacrolimus / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology; D014665:Vasodilator Agents / Q000494:pharmacology / Q000633:toxicity
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D018494:Histamine Agents; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D009569:Nitric Oxide; D003907:Dexamethasone; D006632:Histamine; D002351:Carrageenan; D009195:Peroxidase; D000243:Adenosine Deaminase; D001920:Bradykinin; D016559:Tacrolimus