Abstract
Leishmania donovani (L. donovani) is an obligatory intracellular pathogen that resides and multiplies in the macrophages and has been found to alter the signaling parameters of the host. Testosterone plays a key role as signaling molecules in the regulation of parasite infections and could increase L. donovani infection of macrophages. The mitogen-activated protein kinases (MAPKs) pathway participates in the regulation of functions involved in parasite infection and host defense. In this work, the possibility that modulation of components of MAPK signaling may participate in the L. donovani infection was investigated. We found in this study that L. donovani infection upregulated p38 MAPK of bone marrow-derived macrophage, but not the other MAPK families, extracellular signal-related kinase 1 and 2, and c-jun N-terminal kinase (JNK), as evaluated by Western blotting with specific anti-MAPK antibodies. Moreover, we found that testosterone did not in itself interfere with the MAPKs but attenuated the L. donovani activation of p38 MAPK. The inhibition of p38 MAPK might be responsible for the testosterone-induced higher L. donovani infection since SB203580, a specific inhibitor of p38 MAPK, augmented L. donovani infection too. Collectively, our data indicated that the testosterone-enhanced L. donovani survival in macrophages might be due to the attenuation of MAPK signaling pathway by testosterone.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Beato M, Klug J (2000) Steroid hormone receptors: an update. Hum Reprod Update 6:225–236
Beato M, Chavez S, Truss M (1996) Transcriptional regulation by steroid hormones. Steroids 61:240–251
Benten WPM, Lieberherr M, Giese G, Wrehlke C, Stamm O, Sekeris CE, Mossmann H, Wunderlich F (1999) Functional testosterone receptors in plasma membranes of T cells. FASEB J 13:123–133
Chen CC, Wang JK (1999) p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. Mol Pharmacol 55:481–488
Clark AR, Dean JL, Saklatvala J (2003) Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Lett 546:37–44
Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M (2000) Multiple actions of steroid hormones—a focus on rapid, nongenomic effects. Pharmacol Rev 52:513–556
Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260
Ghosh S, Bhattacharyya S, Sirkar M, Sa GS, Das T, Majumdar D, Roy S, Majumdar S (2002) Leishmania donovani suppresses activated protein 1 and NF-kappaB activation in host macrophages via ceramide generation: involvement of extracellular signal-regulated kinase. Infect Immun 70:6828–6838
Hambleton J, Weinstein SL, Lem L, DeFranco AL (1996) Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci USA 93:2774–2778
Hobbie S, Chen LM, Davis RJ, Galan JE (1997) Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J Immunol 159:5550–5559
Iovannisci DM, Ullman B (1983) High efficiency plating method for Leishmania promastigotes in semi-defined or completely-defined medium. J Parasitol 69:633–636
Ip YT, Davis RJ (1998) Signal transduction by the c-Jun N-terminal kinase (JNK)—from inflammation to development. Curr Opin Cell Biol 10:205–219
Klein SL (2000) The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev 24:627–638
Kracht M, Saklatvala J (2002) Transcriptional and post-transcriptional control of gene expression in inflammation. Cytokine 20:91–106
Kumar S, Boehm J, Lee JC (2003) p38 MAP kinases: key signaling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2:717–726
Liu L, Benten WPM, Wang L, Hao X, Li Q, Zhang H, Guo D, Wang Y, Wunderlich F, Qiao Z (2005) Modulation of Leishmania donovani infection and cell viability by testosterone in bone marrow-derived macrophages: signaling via surface binding sites. Steroids 70:604–614
Losel RM, Falkenstein E, Feuring M, Schultz A, Tillmann HC, Rossol-Haseroth K, Wehling M (2003) Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 83:965–1016
Lu HT, Yang DD, Wysk M, Gatti E, Mellman I, Davis RJ, Flavell RA (1999) Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J 18:1845–1857
Mock BA, Nacy CA (1988) Hormonal modulation of sex differences in resistance to Leishmania major systemic infections. Infect Immun 56:3316–3319
Moore KJ, Labrecque S, Matlashewski G (1993) Alteration of Leishmania donovani infection levels by selective impairment of macrophage signal transduction. J Immunol 150:4457–4465
Mossmann H, Benten WPM, Galanos C, Freudenberg M, Kühn-Velten WN, Reinauer H, Wunderlich F (1997) Dietary testosterone suppresses protective responsiveness to Plasmodium chabaudi malaria. Life Sci 60:839–848
Piedrafita D, Proudfoot L, Nikolaev AV, Xu D, Sands W, Feng GJ, Thomas E, Brewer J, Ferguson MA, Alexander J, Liew FY (1999) Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans. Eur J Immunol 29:235–244
Prive C, Descoteaux A (2000) Leishmania donovani promastigotes evade the activation of mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase-1/2 during infection of naïve macrophages. Eur J Immunol 30:2235–2244
Proudfoot L, Nikolaev A, Feng GL, Wei XQ, Ferguson MAJ, Brimacombe JS, Liew FY (1996) Regulation of expression of nitric oxide synthase and leishmanicidal activity by glycoconjugates of Leishmania lipophosphoglycan in murine macrophages. Proc Natl Acad Sci USA 93:10984–10989
Reiner NE (1982) Host–parasite relationship in murine leishmaniasis: pathophysiological and immunological changes. Infect Immun 38:1223–1230
Roberts CW, Satoskar A, Alexander J (1996) Sex steroids, pregnancy-associated hormones and immunity to parasitic infection. Parasitol Today 12:382–388
Robinson MJ, Cobb MH (1997) Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186
Tang P, Sutherland CL, Gold MR, Finlay BB (1998) Listeria monocytogenes invasion of epithelial cells requires the MEK-1/ERK-2 mitogen-activated protein kinase pathway. Infect Immun 66:1106–1112
Wunderlich F, Benten WPM, Lieberherr M, Guo Z, Stamm O, Wrehlke C, Sekeris CE, Mossmann H (2002) Testosterone signaling in T cells and macrophages. Steroids 67:535–538
Yin G, Guo Z, Yin L, Zhao J, Qiao Z, Wunderlich F (1998) Effect of testosterone on Leishmania donovani infection levels of murine bone marrow derived-macrophages. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 16:251–255
Acknowledgements
This work was completed in Shanghai Jiaotong University. We are grateful to Yao CJ, Zhou Y, Lu M, Zhang ZM, Chen XL, and Fang XK for their assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liu, L., Wang, L., Zhao, Y. et al. Testosterone attenuates p38 MAPK pathway during Leishmania donovani infection of macrophages. Parasitol Res 99, 189–193 (2006). https://doi.org/10.1007/s00436-006-0168-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-006-0168-1