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The Required Role of Endogenously Produced Lipoxin A₄ and Annexin-1 for the Production of IL-10 and Inflammatory Hyporesponsiveness in Mice¹

Danielle G. Souza^*,, Caio T. Fagundes^*,, Flavio A. Amaral^*,, Daniel Cisalpino^*,, Lirlândia P. Sousa^*, Angélica T. Vieira^*, Vanessa Pinho^*,, Jacques R. Nicoli, Leda Q. Vieira^*, Iolanda M. Fierro and Mauro M. Teixeira^2,*

^* Departamento de Bioquímica e Imunologia; Departamento de Microbiologia; Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; and Departamento de Farmacologia, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

The appropriate development of an inflammatory response is central for the ability of a host to deal with any infectious insult. However, excessive, misplaced, or uncontrolled inflammation may lead to acute or chronic diseases. The microbiota plays an important role in the control of inflammatory responsiveness. In this study, we investigated the role of lipoxin A₄ and annexin-1 for the IL-10-dependent inflammatory hyporesponsiveness observed in germfree mice. Administration of a 15-epi-lipoxin A₄ analog or an annexin-1-derived peptide to conventional mice prevented tissue injury, TNF- production, and lethality after intestinal ischemia/reperfusion. This was associated with enhanced IL-10 production. Lipoxin A₄ and annexin-1 failed to prevent reperfusion injury in IL-10-deficient mice. In germfree mice, there was enhanced expression of both lipoxin A₄ and annexin-1. Blockade of lipoxin A₄ synthesis with a 5-lipoxygenase inhibitor or Abs against annexin-1 partially prevented IL-10 production and this was accompanied by partial reversion of inflammatory hyporesponsiveness in germfree mice. Administration of BOC-1, an antagonist of ALX receptors (at which both lipoxin A₄ and annexin-1 act), or simultaneous administration of 5-lipoxygenase inhibitor and anti-annexin-1 Abs, was associated with tissue injury, TNF- production, and lethality similar to that found in conventional mice. Thus, our data demonstrate that inflammatory responsiveness is tightly controlled by the presence of the microbiota and that the innate capacity of germfree mice to produce IL-10 is secondary to their endogenous greater ability to produce lipoxin A₄ and annexin-1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Fundação de Amparo à Pesquisa do Estado de Minas Gerais and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico.

² Address correspondence and reprint requests to Dr. Mauro Martins Teixeira, Departamento de Bioquímica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627–Pampulha, Brazil. E-mail address: mmtex{at}icb.ufmg.br

³ Abbreviations used in this paper: LXA₄, lipoxin A₄; ANXA-1, annexin-1; SMA, superior mesenteric artery; PMN, polymorphonuclear; LT, leukotriene.

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