Diethylcarbamazine inhibits NF-κB activation in acute lung injury induced by carrageenan in mice Laise Aline Martins Santos a, ⁎, Edlene Lima Ribeiro a , Karla Patrícia Sousa Barbosa a , Ingrid Tavares Fragoso a , Fabiana Oliveira dos Santos Gomes a , Mariana Aragão Matos Donato a , Bruna Santos Silva a , Amanda Karolina Soares Silva a , Sura Wanessa Santos Rocha a , Maria Eduarda Rocha França a , Gabriel Barros Rodrigues a , Teresinha Gonçalves Silva b , Christina Alves Peixoto a a Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, CPqAM/FIOCRUZ, Brazil b Departamento de Antibióticos, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Brazil abstract article info Article history: Received 7 July 2014 Received in revised form 12 August 2014 Accepted 18 August 2014 Available online 28 August 2014 Keywords: Diethylcarbamazine Nuclear transcription factor-κB Pleurisy Mitogen-activated protein kinases Diethylcarbamazine citrate (DEC) is widely used to treat lymphatic filariasis and Tropical Pulmonary Eosinophilia. A number of studies have reported a possible role in the host immune system, but exactly how DEC exerts this effect is still unknown. The present study reports the effects of DEC pretreatment on NF-κB regulation using the pleurisy model induced by carrageenan. Swiss male mice (Mus musculus) were divided into four experimen- tal groups: control (SAL); carrageenan (CAR); diethylcarbamazine (DEC) and curcumin (CUR). The animals were pretreated with DEC (50 mg/kg, v.o), CUR(50 mg/kg, i.p) or distilled water for three consecutive days before pleurisy. One way analysis of variance (ANOVA) was performed by Tukey post-hoc test, and values were consid- ered statistically significant when p b 0.05. DEC pretreatment reduced tissue damage and the production of inflammatory markers, such as NO, iNOS, PGE2, COX-2, and PARP induced by carrageenan. Similarly, a known inhibitor of NF-κB pathway (curcumin) was also able to reduce these parameters. Like curcumin, DEC prevents NF-κB activation by reducing NF-κB p65 phosphorylation and IκBα degradation. DEC prevented NF-κB activation via p38 MAPK, but did not interfere in the ERK pathway in this experimental model. However, further studies should be developed to confirm this hypothesis. These findings suggest that DEC could be a promising drug for inflammatory disorders, especially in pulmonary diseases such as Acute Lung Inflammation, due its high anti- inflammatory potential which prevents NF-κB activation. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Diethylcarbamazine (DEC) is a piperazine derivative that is widely used to treat lymphatic filariasis. Its mechanism of action remains un- clear, although evidence suggests a possible action on the host immune system [1,2]. The effectiveness of DEC in the treatment of Tropical Pul- monary Eosinophilia (TPE) in clinical studies confirms this hypothesis and may be a potential indication for the use of this drug in other lung diseases such as COPD and ALI [3]. Recently, a number of studies have reported a marked anti-inflammatory property for DEC using asthma and acute lung injury models [4,5]. However, how DEC exerts this effect is still unknown, and no existing studies have investigated the effect of DEC in relation to key transcription factors that orchestrate the inflam- matory response. The nuclear transcription factor-κB (NF-κB) regulates the expression of numerous components of the immune system [6]. NF-κB is a critical intracellular mediator of the inflammatory cascade, which can trigger the expression of multiple inflammatory genes, including tumor necro- sis factor-α (TNF-α) and interleukin-1β (IL-1β) [7]. Several studies have suggested that the regulation of nuclear transcription factor-κB (NF-κB) could be a potential therapeutic target for the treatment of acute pulmonary inflammation [8]. NF-κB proteins exist as inactive dimers in the cytoplasm bound to IκB-α, its inhibitory enzyme. After an injury, a specificIκB-kinase complex phosphorylates and degrades IκBα through the proteasome. The IκBα degradation allows NF-κB to translocate into the nucleus where it acts as a transcription factor for the generation of inflammation International Immunopharmacology 23 (2014) 153–162 Abbreviations: NO, nitric oxide; iNOS, inducible nitric oxide synthase; PGE2, prosta- glandin E2; COX-2, cyclooxygenase-2; PARP, poly (ADP-ribose) polymerase; NF-κB, nucle- ar transcription factor-κB; MAPKs, mitogen-activated protein kinases. ⁎ Corresponding author at: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, CPqAM/FIOCRUZ. Av. Professor Moraes Rego, s/n, Campus da UFPE, Cidade Universitária CEP: 50.670-420 Recife, Brazil. Tel.:+55 81 2101 2583. E-mail addresses: laisealine@gmail.com (L.A.M. Santos), edlenelimaribeiro@gmail.com (E.L. Ribeiro), karlapsb@gmail.com (K.P.S. Barbosa), ingridtavaresfragoso@hotmail.com (I.T. Fragoso), gomes.bio@gmail.com (F.O.S. Gomes), maridonato@gmail.com (M.A.M. Donato), ssbruna@gmail.com (B.S. Silva), kls.amanda@gmail.com (A.K.S. Silva), surawanessa@gmail.com (S.W.S. Rocha), mariaeduarda.rfranca@gmail.com (M.E.R. França), gabrielb.rodrigues@hotmail.com (G.B. Rodrigues), teresinha100@gmail.com (T.G. Silva), peixoto.christina@gmail.com (C.A. Peixoto). http://dx.doi.org/10.1016/j.intimp.2014.08.017 1567-5769/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp