ABCC transporter inhibition reduces zymosan-induced peritonitis.
Inflammatory mediators are released from injured tissues being responsible for the first steps of inflammatory processes. Multidrug efflux transporters, members of the ATP-binding cassette (ABC) family, are ubiquitously expressed. ABCC molecules transport several endogenous substances, including leukotriene C4 (LTC4) and PGE2, which are involved in zymosan-induced inflammation. The present study investigated the role played by ABCC transporters on zymosan-induced peritonitis in mice. Most of the resident peritoneal cells were macrophages, based on their morphology and membrane-activated complex 3 expression. RT-PCR demonstrated that these cells expressed ABCC, and ABCC activity was analyzed in vivo via the s.c. injection of ABCC inhibitors [probenecid (PROB) 200 mg/kg or MK571 20 mg/kg], followed by an i.v. injection of carboxyfluorescein diacetate (CFDA), an ABCC fluorescent substrate. Both inhibitors increased CFDA accumulation, suggesting ABCC impairment. Moreover, ABCC reversors decreased zymosan-induced plasma exudation by 86.6 +/- 7.4 and 97.6 +/- 2.3%, a feature related to a diminished secretion of LTC(4) (65.1+/-11 and 47.8+/-9.9%) and PGE(2) (under basal levels). Cell migration was inhibited similarly. Furthermore, PROB and MK571 inhibited IL-1ss by 83.4 +/- 13 and 71.2 +/- 13.4% and TNF-alpha content by 47 +/- 4.5 and 28.9 +/- 0.8%, respectively. NO metabolites and reactive oxygen species production were also reduced. The present results suggest that ABCC molecules have a relevant role in the acute inflammatory response produced by zymosan in mice.
Leite
Daniela F P
DF
Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil.
Echevarria-Lima
Juliana
J
Ferreira
Samira Cardoso
SC
Calixto
João B
JB
Rumjanek
Vivian M
VM
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001993:Bronchodilator Agents / Q000494:pharmacology; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D004487:Edema / Q000517:prevention & control; D015777:Eicosanoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D049449:Luminescence; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000517:prevention & control*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D016897:Respiratory Burst; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015054:Zymosan / Q000633:toxicity*
D000943:Antigens, Differentiation; D001993:Bronchodilator Agents; D015777:Eicosanoids; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; C036763:monocyte-macrophage differentiation antigen; C059141:verlukast; C421109:multidrug resistance-associated protein 1