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Published online before print June 18, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0107042

Received for publication January 19, 2007.
Revised May 4, 2007.
Accepted for publication May 17, 2007.

Article

ABCC transporter inhibition reduces zymosan-induced peritonitis

Daniela F. P. Leite *{dagger}{ddagger}, Juliana Echevarria-Lima {sect}, Samira Cardoso Ferreira ||, João B. Calixto {ddagger}, and Vivian M. Rumjanek *@

Institutos de *Bioquímica Médica and {dagger}Biofísica Carlos Chagas Filho and {sect}Departamento de Imunologia, Instituto de Microbiologia Paulo Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil; and {ddagger}Departamento de Farmacologia and ||Hospital Universitário, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil

@ To whom correspondence should be addressed. E-mail: vivian{at}bioqmed.ufrj.br.


  Abstract

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 LTC4 (65.1±11 and 47.8±9.9%) and PGE2 (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.

Key Words: CFDA • LTC4 • NOx • ROS






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