Cholecystokinin protects rats against sepsis induced by Staphylococcus aureus
- 319 Downloads
Staphylococcus aureus is a Gram-positive bacteria described as an important causative agent of sepsis. The contact between host leukocytes and bacteria activates the innate immune response. Nitric oxide, tumor necrosis factor (TNF)-α and interleukin (IL)-1β play a key role in increasing microbicidal activity and controlling cell influx into infectious focus. Contrarily, IL-10 acts as an anti-inflammatory cytokine and bacterial killing suppressor. Immunoregulatory properties have also been attributed to hormones, including cholecystokinin (CCK). CCK protects cardiovascular function and inhibits the inflammatory response induced by lipopolysaccharide, product derived from Gram-negative bacteria. Nevertheless, the role of CCK during Gram-positive infection remains a literature gap. Our aims were to investigate whether CCK protects rats against bacterial dissemination during sepsis induced by S. aureus. We determined whether CCK modulates local and systemic inflammatory response, as well as the cell migration into the infectious focus and the bactericidal capacity of leukocytes. Our results revealed that proglumide (nonselective CCK receptor antagonist) pretreated rats showed higher bacterial counts in blood and peritoneal lavage fluid (PLF) and reduced TNF-α and IL-10 levels in PLF. Moreover, the dissemination of S. aureus may be related to the failure of neutrophil and macrophage migration into the peritoneal cavity. Also, CCK improved the phagocytic and bactericidal ability of these inflammatory cells. Noteworthy is that the adoptive transfer of CCK-treated neutrophils and macrophages in septic rats improved immune defense, reducing bacterial number in blood and PLF. All together, our study clearly demonstrates an important protective role of CCK against sepsis induced by S. aureus.
KeywordsCCK Nitric oxide Proglumide Cell migration Macrophage Neutrophil
We would like to thank Marcelo Eduardo Batalhão for the technical assistance. The authors gratefully acknowledge the English grammar review by Renata Brancaleoni Mitchell and Ian Mitchell. This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).
Conflict of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
- 5.Marra AR, Camargo LF, Pignatari AC, Sukiennik T, Behar PR, Medeiros EA, Ribeiro J, Girao E, Correa L, Guerra C, Brites C, Pereira CA, Carneiro I, Reis M, de Souza MA, Tranchesi R, Barata CU, Edmond MB (2011) Nosocomial bloodstream infections in Brazilian hospitals: analysis of 2,563 cases from a prospective nationwide surveillance study. J Clin Microbiol 49(5):1866–1871. doi: 10.1128/JCM.00376-11 PubMedCentralPubMedCrossRefGoogle Scholar
- 23.Miyamoto S, Shikata K, Miyasaka K, Okada S, Sasaki M, Kodera R, Hirota D, Kajitani N, Takatsuka T, Kataoka HU, Nishishita S, Sato C, Funakoshi A, Nishimori H, Uchida HA, Ogawa D, Makino H (2012) Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: anti-inflammatory effect of cholecystokinin. Diabetes 61(4):897–907. doi: 10.2337/db11-0402 PubMedCentralPubMedCrossRefGoogle Scholar
- 24.Alvarez A, Ibiza S, Hernandez C, Alvarez-Barrientos A, Esplugues JV, Calatayud S (2006) Gastrin induces leukocyte-endothelial cell interactions in vivo and contributes to the inflammation caused by Helicobacter pylori. FASEB J 20(13):2396–2398. doi: 10.1096/fj.05-5696fje PubMedCrossRefGoogle Scholar
- 25.Saia RS, Oliveira-Pelegrin GR, da Silva ME, Aguila FA, Antunes-Rodrigues J, Rocha MJ, Carnio EC (2011) Neonatal endotoxin exposure changes neuroendocrine, cardiovascular function and mortality during polymicrobial sepsis in adult rats. Regul Pept 169(1–3):21–30. doi: 10.1016/j.regpep.2011.04.009 PubMedCrossRefGoogle Scholar
- 31.Bercik P, Verdu EF, Foster JA, Lu J, Scharringa A, Kean I, Wang L, Blennerhassett P, Collins SM (2009) Role of gut-brain axis in persistent abnormal feeding behavior in mice following eradication of Helicobacter pylori infection. Am J Physiol 296(3):R587–R594. doi: 10.1152/ajpregu.90752.2008 Google Scholar
- 34.Grivennikov SI, Tumanov AV, Liepinsh DJ, Kruglov AA, Marakusha BI, Shakhov AN, Murakami T, Drutskaya LN, Forster I, Clausen BE, Tessarollo L, Ryffel B, Kuprash DV, Nedospasov SA (2005) Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity 22(1):93–104. doi: 10.1016/j.immuni.2004.11.016 PubMedGoogle Scholar
- 35.van den Berg S, Laman JD, Boon L, ten Kate MT, de Knegt GJ, Verdijk RM, Verbrugh HA, Nouwen JL, Bakker-Woudenberg IA (2013) Distinctive cytokines as biomarkers predicting fatal outcome of severe Staphylococcus aureus bacteremia in mice. PLoS ONE 8(3):e59107. doi: 10.1371/journal.pone.0059107 PubMedCentralPubMedCrossRefGoogle Scholar
- 39.Berg DJ, Kuhn R, Rajewsky K, Muller W, Menon S, Davidson N, Grunig G, Rennick D (1995) Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J Clin Invest 96(5):2339–2347. doi: 10.1172/JCI118290 PubMedCentralPubMedCrossRefGoogle Scholar
- 43.Tavares-Murta BM, Cunha FQ, Ferreira SH (1998) The intravenous administration of tumor necrosis factor alpha, interleukin 8 and macrophage-derived neutrophil chemotactic factor inhibits neutrophil migration by stimulating nitric oxide production. Br J Pharmacol 124(7):1369–1374. doi: 10.1038/sj.bjp.0701965 PubMedCentralPubMedCrossRefGoogle Scholar
- 44.Ajuebor MN, Das AM, Virag L, Flower RJ, Szabo C, Perretti M (1999) Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: evidence for an inhibitory loop involving endogenous IL-10. J Immunol 162(3):1685–1691PubMedGoogle Scholar