Leishmania mexicana: Participation of NF-jB in the differential production of IL-12 in dendritic cells and monocytes induced by lipophosphoglycan (LPG) Jesús Argueta-Donohué a , Nuria Carrillo a , Leonardo Valdés-Reyes a , Alejandro Zentella b , Magdalena Aguirre-García a , Ingeborg Becker a , Laila Gutiérrez-Kobeh a, * a Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Dr. Balmis 148, Col. Doctores, México 06726, Mexico b Departamento de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición ‘‘Salvador Zubirán”, Secretaría de Salud, C. P. 14000, México, Mexico article info Article history: Received 5 July 2007 Received in revised form 29 February 2008 Accepted 3 April 2008 Available online 11 April 2008 Index Descriptors and Abbreviations: Leishmania mexicana LPG Dendritic cells (DC) Monocyte-derived dendritic cells (moDC) Macrophages (Mu) Monocytes IL-12 IL-10 TNF-a NF-jB abstract Dendritic cells (DC) and macrophages (Mu) are well known as important effectors of the innate immune system and their ability to produce IL-12 indicates that they possess the potential of directing acquired immunity toward a Th1-biased response. Interestingly, the intracellular parasite Leishmania has been shown to selectively suppress Mu IL-12 production and are DC the principal source of this cytokine. The molecular details of this phenomenon remain enigmatic. In the present study we examined the effect of Leishmania mexicana lipophosphoglycan (LPG) on the production of IL-12, TNF-a, and IL-10 and nuclear translocation of NF-jB. The results show that LPG induced more IL-12 in human DC than in monocytes. This difference was due in part to nuclear translocation of NF-jB, since LPG induced more translocation in DC than in monocytes. These results suggest that Leishmania LPG impairs nuclear translocation of NF-jB in monocytes with the subsequent decrease in IL-12 production. Ó 2008 Elsevier Inc. All rights reserved. 1. Introduction Leishmania are dimorphic protozoan parasites which are trans- mitted by the phlebotomine sandfly to mammalian hosts where they become obligate intracellular parasites that reside primarily within macrophages (Mu) and dendritic cells (DC). Leishmania species cause a wide range of pathologies in humans and may be fatal if left untreated. Mu are well known as important effectors of the innate immune system, and their ability to produce IL-12 indicates that they possess the potential of directing acquired immunity toward a Th1-biased response. DC are the most potent type of antigen-pre- senting cells (APC) and play a critical role in the initiation of immu- nity by producing soluble factors, chemokines and cytokines. In cutaneous leishmaniasis Mu ingest promastigotes, but they are not activated and are rendered selectively unable to produce the Th1-promoting cytokine IL-12 in response to inflammatory mediators (Reiner and Locksley, 1995; Carrera et al., 1996; Belkaid et al., 1998). In contrast, different studies have shown that murine fetal-skin-derived DC (von Stebut et al., 1998, 2000), murine sple- nic DC (Gorak et al., 1998; Konecny et al., 1999) and blood-derived human DC (Marovich et al., 2000) produce IL-12 following infec- tion with Leishmania. Implicit in the findings that Leishmania can modulate IL-12 production in DC and Mu is that these cells can recognize parasite-derived molecules. DC and Vu are thought to distinguish different pathogens through the recognition of patho- gen-associated molecular patterns (PAMP) via the expression of pattern recognition receptors (PRR), such as the Toll like receptor family that decode the microbial surface proteins (Gordon, 2002; Janeway and Medzhitov, 2002; Medzhitov and Janeway, 2002; Akira, 2003). For Leishmania, the major surface glycoconjugate is LPG and is expressed by all Leishmania species. As many as 10 6 cop- ies of LPG are present on a single promastigote (Orlandi and Turco, 1987), suggesting a role for this macromolecule for parasite–host interaction. Recent studies with LPG purified from Leishmania major indicate that LPG interacts with DC, i.e., Langerhans cells (Ponte-Sucre et al., 2001), can bind to human TLR2 on transfected cells (de Veer et al., 2003), NK cells (Becker et al., 2003), and induces proinflammatory cytokines in murine macrophage lines (de Veer et al., 2003), suggesting that LPG may act as a PAMP. Also, the differences in IL-12 production between DC and Mu could be due to differences in IL-12 transcription. The bioactive IL-12p70 is a heterodimeric protein consisting of covalently linked p40 and p35 subunits, both of which are regulated independently 0014-4894/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.exppara.2008.04.002 * Corresponding author. Fax: +5255 5761 02 49. E-mail address: lgutierr@servidor.unam.mx (L. Gutiérrez-Kobeh). Experimental Parasitology 120 (2008) 1–9 Contents lists available at ScienceDirect Experimental Parasitology journal homepage: www.elsevier.com/locate/yexpr