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* Department of Pharmacology,
Department of Surgery and Anatomy, and
Department of Pathology, School of Medicine of Ribeirão Preto, Ribeirão Preto, Brazil;
Department of Pharmaceutical Science, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil; and
¶ Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceara, Fortaleza, Ceara, Brazil
In this study, we have addressed the role of H2S in modulating neutrophil migration in either innate (LPS-challenged naive mice) or adaptive (methylated BSA (mBSA)-challenged immunized mice) immune responses. Treatment of mice with H2S synthesis inhibitors, DL-propargylglycine (PAG) or β-cyanoalanine, reduced neutrophil migration induced by LPS or methylated BSA (mBSA) into the peritoneal cavity and by mBSA into the femur/tibial joint of immunized mice. This effect was associated with decreased leukocyte rolling, adhesion, and P-selectin and ICAM-1 expression on endothelium. Predictably, treatment of animals with the H2S donors, NaHS or Lawesson’s reagent, enhanced these parameters. Moreover, the NaHS enhancement of neutrophil migration was not observed in ICAM-1-deficient mice. Neither PAG nor NaHS treatment changed LPS-induced CD18 expression on neutrophils, nor did the LPS- and mBSA-induced release of neutrophil chemoattractant mediators TNF-
, keratinocyte-derived chemokine, and LTB4. Furthermore, in vitro MIP-2-induced neutrophil chemotaxis was inhibited by PAG and enhanced by NaHS treatments. Accordingly, MIP-2-induced CXCR2 internalization was enhanced by PAG and inhibited by NaHS treatments. Moreover, NaHS prevented MIP-2-induced CXCR2 desensitization. The PAG and NaHS effects correlated, respectively, with the enhancement and inhibition of MIP-2-induced G protein-coupled receptor kinase 2 expression. The effects of NaHS on neutrophil migration both in vivo and in vitro, together with CXCR2 internalization and G protein-coupled receptor kinase 2 expression were prevented by the ATP-sensitive potassium (KATP+) channel blocker, glybenclamide. Conversely, diazoxide, a KATP+ channel opener, increased neutrophil migration in vivo. Together, our data suggest that during the inflammatory response, H2S augments neutrophil adhesion and locomotion, by a mechanism dependent on KATP+ channels.
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1 This work was supported by Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Fundação de Amparo à Pesquisa do Estado de Sao Paulo, and Conselho Nacional de Pesquisa.
2 Address correspondence and reprint requests to Prof. Dr. Fernando de Queiroz Cunha, Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900-Ribeirão Preto, São Paulo, Brazil. E-mail address: fdqcunha{at}fmrp.usp.br
3 Abbreviations used in this paper: LTB4, leukotriene B4; PAG, DL-propargylglycine; BCA, β-cyanoalanine; GRK, G protein-coupled receptor kinase; CSE, cystathionine-
-lyase; WT, wild type; KC, keratinocyte-derived chemokine; mBSA, methylated BSA; AU, arbitrary units; FI, false immunized; i.a., intra-articular; NSAID, anti-inflammatory drug.
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