Hostname: page-component-8448b6f56d-jr42d Total loading time: 0 Render date: 2024-04-20T04:14:46.743Z Has data issue: false hasContentIssue false
  • English
  • Français

Leishmania mexicana lipophosphoglycan activates ERK and p38 MAP kinase and induces production of proinflammatory cytokines in human macrophages through TLR2 and TLR4

Published online by Cambridge University Press:  05 February 2014

A. ROJAS-BERNABÉ ,
O. GARCIA-HERNÁNDEZ ,
C. MALDONADO-BERNAL ,
J. DELEGADO-DOMINGUEZ ,
E. ORTEGA ,
L. GUTIÉRREZ-KOBEH ,
I. BECKER  and
M. AGUIRRE-GARCIA
A. ROJAS-BERNABÉ
Affiliation:
Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México
O. GARCIA-HERNÁNDEZ
Affiliation:
Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México
C. MALDONADO-BERNAL
Affiliation:
Unidad de Investigación de Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, México, D.F., México
J. DELEGADO-DOMINGUEZ
Affiliation:
Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México
E. ORTEGA
Affiliation:
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, D.F., México
L. GUTIÉRREZ-KOBEH
Affiliation:
Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México
I. BECKER
Affiliation:
Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México
M. AGUIRRE-GARCIA*
Affiliation:
Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México
*
*Corresponding author. Departmento de Medicina Experimental, Facultad de Medicina, UNAM, Dr. Balmis 148, Colonia Doctores, México, D.F., 06726, México. E-mail: maguirre@unam.mx
Get access Rights & Permissions [Opens in a new window]

Summary

Protozoan parasites of genus Leishmania are the causative agents of leishmaniasis. Leishmania promastigotes primarily infect macrophages in the host, where they transform into amastigotes and multiply. Lipophosphoglycan (LPG), the most abundant surface molecule of the parasite, is a virulence determinant that regulates the host immune response. Promastigotes are able to modulate this effect through LPG, creating a favourable environment for parasite survival, although the mechanisms underlying this modulation remain unknown. We analysed the participation of TLR2 and TLR4 in the production of cytokines and explored the possible phosphorylation of ERK and/or p38 MAP kinase signalling cascades in human macrophages stimulated with Leishmania mexicana LPG. The results show that LPG induced the production of TNF-α, IL-1β, IL-12p40, IL-12p70 and IL-10 and led to phosphorylation of ERK and p38 MAP kinase. Specific inhibitors of ERK or p38 MAP kinases and mAbs against TLR2 and TLR4 reduced cytokine production and phosphorylation of both kinases. Our results suggest that L. mexicana LPG binds TLR2 and TLR4 receptors in human macrophages, leading to ERK and MAP kinase phosphorylation and production of pro-inflammatory cytokines.

Keywords

ERKp38 MAP kinaseLeishmania mexicanalipophosphoglycanhuman macrophages
Type
Research Article
Information
Parasitology , Volume 141 , Issue 6 , May 2014 , pp. 788 - 800
Check for updates
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Argueta-Donohue, J., Carrillo, N., Valdes-Reyes, L., Zentella, A., Aguirre-Garcia, M., Becker, I. and Gutierrez-Kobeh, L. (2008). Leishmania mexicana: participation of NF-kappaB in the differential production of IL-12 in dendritic cells and monocytes induced by lipophosphoglycan (LPG). Experimental Parasitology 120, 1–9. doi: S0014-4894(08)00095-7 [pii] 10.1016/j.exppara.2008.04.002.Google Scholar
Balaraman, S., Singh, V. K., Tewary, P. and Madhubala, R. (2005). Leishmania lipophosphoglycan activates the transcription factor activating protein 1 in J774A.1 macrophages through the extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase. Molecular Biochemical Parasitology 139, 117–127. doi: S0166-6851(04)00302-0 [pii] 10.1016/j.molbiopara.2004.10.006.Google Scholar
Becker, I., Salaiza, N., Aguirre, M., Delgado, J., Carrillo-Carrasco, N., Kobeh, L. G., Ruiz, A., Cervantes, R., Torres, A. P., Cabrera, N., Gonzalez, A., Maldonado, C. and Isibasi, A. (2003). Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2. Molecular Biochemical Parasitology 130, 65–74. doi: S0166685103001609 [pii].Google Scholar
Ben-Othman, R., Guizani-Tabbane, L. and Dellagi, K. (2008). Leishmania initially activates but subsequently down-regulates intracellular mitogen-activated protein kinases and nuclear factor-kappaB signaling in macrophages. Molecular Immunology 45, 3222–3229. doi: S0161-5890(08)00094-1 [pii] 10.1016/j.molimm.2008.02.019.Google Scholar
Ben-Othman, R., Dellagi, K. and Guizani-Tabbane, L. (2009). Leishmania major parasites induced macrophage tolerance: implication of MAPK and NF-kappaB pathways. Molecular Immunology 46, 3438–3444. doi: S0161-5890(09)00246-6 [pii] 10.1016/j.molimm.2009.05.337.CrossRefGoogle ScholarPubMed
Carrada, G., Caneda, C., Salaiza, N., Delgado, J., Ruiz, A., Sanchez, B., Gutierrez-Kobeh, L., Aguirre, M. and Becker, I. (2007). Monocyte cytokine and costimulatory molecule expression in patients infected with Leishmania mexicana . Parasite Immunology 29, 117–126. doi: PIM924 [pii] 10.1111/j.1365-3024.2006.00924.x.Google Scholar
Chandra, D. and Naik, S. (2008). Leishmania donovani infection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanism. Clinical Experimental Immunology 154, 224–234. doi: CEI3741 [pii]10.1111/j.1365-2249.2008.03741.x.CrossRefGoogle ScholarPubMed
Delgado-Dominguez, J., Gonzalez-Aguilar, H., Aguirre-Garcia, M., Gutierrez-Kobeh, L., Berzunza-Cruz, M., Ruiz-Remigio, A., Robles-Flores, M. and Becker, I. (2010). Leishmania mexicana lipophosphoglycan differentially regulates PKCalpha-induced oxidative burst in macrophages of BALB/c and C57BL/6 mice. Parasite Immunology 32, 440–449. doi: PIM1205 [pii] 10.1111/j.1365-3024.2010.01205.x.CrossRefGoogle ScholarPubMed
Del Vecchio, M., Bajetta, E., Canova, S., Lotze, M. T., Wesa, A., Parmiani, G. and Anichini, A. (2007). Interleukin-12: biological properties and clinical application. Clinical Cancer Research 13, 4677–4685. doi: 13/16/4677 [pii] 10.1158/1078-0432.CCR-07-0776.Google Scholar
de Veer, M. J., Curtis, J. M., Baldwin, T. M., DiDonato, J. A., Sexton, A., McConville, M. J., Handman, E. and Schofield, L. (2003). MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll-like receptor 2 signaling. European Journal Immunology 33, 2822–2831. doi: 10.1002/eji.200324128.Google Scholar
Feng, G. J., Goodridge, H. S., Harnett, M. M., Wei, X. Q., Nikolaev, A. V., Higson, A. P. and Liew, F. Y. (1999). Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase. Journal of Immunology 163, 6403–6412. doi: ji_v163n12p6403 [pii].CrossRefGoogle ScholarPubMed
Flandin, J. F., Chano, F. and Descoteaux, A. (2006). RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon-gamma-primed macrophages. European Journal Immunology 36, 411–420. doi: 10.1002/eji.200535079.CrossRefGoogle ScholarPubMed
Gallego, C., Golenbock, D., Gomez, M. A. and Saravia, N. G. (2011). Toll-like receptors participate in macrophage activation and intracellular control of Leishmania (Viannia) panamensis . Infection and Immunology 79, 2871–2879. doi: IAI.01388-10 [pii]10.1128/IAI.01388-10.Google Scholar
Ibraim, I. C., de Assis, R. R., Pessoa, N. L., Campos, M. A., Melo, M. N., Turco, S. J. and Soares, R. P. (2013). Two biochemically distinct lipophosphoglycans from Leishmania braziliensis and Leishmania infantum trigger different innate immune responses in murine macrophages. Parasite Vectors 6, 54. doi: 1756-3305-6-54 [pii] 10.1186/1756-3305-6-54.Google Scholar
Jung, S. B., Yang, C. S., Lee, J. S., Shin, A. R., Jung, S. S., Son, J. W., Harding, C. V., Kim, H. J., Park, J. K., Paik, T. H., Song, C. H. and Jo, E. K. (2006). The mycobacterial 38-kilodalton glycolipoprotein antigen activates the mitogen-activated protein kinase pathway and release of proinflammatory cytokines through Toll-like receptors 2 and 4 in human monocytes. Infection and Immunology 74, 2686–2696. doi: 74/5/2686 [pii] 10.1128/IAI.74.5.2686-2696.2006.CrossRefGoogle ScholarPubMed
Junghae, M. and Raynes, J. G. (2002). Activation of p38 mitogen-activated protein kinase attenuates Leishmania donovani infection in macrophages. Infection and Immunology 70, 5026–5035.Google Scholar
Kavoosi, G., Ardestani, S. K. and Kariminia, A. (2009). The involvement of TLR2 in cytokine and reactive oxygen species (ROS) production by PBMCs in response to Leishmania major phosphoglycans (PGs). Parasitology 136, 1193–1199. doi: S0031182009990473 [pii] 10.1017/S0031182009990473.Google Scholar
Kropf, P., Freudenberg, M. A., Modolell, M., Price, H. P., Herath, S., Antoniazi, S., Galanos, C., Smith, D. F. and Muller, I. (2004). Toll-like receptor 4 contributes to efficient control of infection with the protozoan parasite Leishmania major . Infection and Immunology 72, 1920–1928.Google Scholar
Kyriakis, J. M. and Avruch, J. (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiology Review 81, 807–869.CrossRefGoogle ScholarPubMed
Li, C. H., Wang, J. H. and Redmond, H. P. (2006). Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation. Journal of Leukocyte Biology 79, 867–875. doi: jlb.0905505 [pii] 10.1189/jlb.0905505.CrossRefGoogle ScholarPubMed
Liese, J., Schleicher, U. and Bogdan, C. (2008). The innate immune response against Leishmania parasites. Immunobiology 213, 377–387. doi: S0171-2985(08)00003-X [pii] 10.1016/j.imbio.2007.12.005.Google Scholar
Lu, H. T., Yang, D. D., Wysk, M., Gatti, E., Mellman, I., Davis, R. J. and Flavell, R. A. (1999). Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO Journal 18, 1845–1857. doi: 10.1093/emboj/18.7.1845.Google Scholar
Mathur, R. K., Awasthi, A., Wadhone, P., Ramanamurthy, B. and Saha, B. (2004). Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nature Medicine 10, 540–544. doi: 10.1038/nm1045 nm1045 [pii].Google Scholar
Means, T. K., Golenbock, D. T. and Fenton, M. J. (2000). The biology of Toll-like receptors. Cytokine Growth Factor Reviews 11, 219–232. doi: S1359-6101(00)00006-X [pii].CrossRefGoogle ScholarPubMed
Naderer, T., Vince, J. E. and McConville, M. J. (2004). Surface determinants of Leishmania parasites and their role in infectivity in the mammalian host. Current Molecular Medicine 4, 649–665.Google Scholar
Nomura, F., Akashi, S., Sakao, Y., Sato, S., Kawai, T., Matsumoto, M., Nakanishi, K., Kimoto, M., Miyake, K., Takeda, K. and Akira, S. (2000). Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression. Journal of Immunology 164, 3476–3479. doi: ji_v164n7p3476 [pii].CrossRefGoogle ScholarPubMed
Prive, C. and 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 naive macrophages. European Journal of Immunology 30, 2235–2244. doi: 10.1002/1521-.CO;2-9 [pii] 10.1002/1521-4141(2000)30:8<2235::AID-IMMU2235>3.0.CO;2-9.Google Scholar
Robinson, M. J. and Cobb, M. H. (1997). Mitogen-activated protein kinase pathways. Current Opinion in Cell Biology 9, 180–186. doi: S0955-0674(97)80061-0 [pii].Google Scholar
Sharma, U. and Singh, S. (2009). Immunobiology of leishmaniasis. Indian Journal of Experimental Biology 47, 412–423.Google ScholarPubMed
Shweash, M., Adrienne McGachy, H., Schroeder, J., Neamatallah, T., Bryant, C. E., Millington, O., Mottram, J. C., Alexander, J. and Plevin, R. (2011). Leishmania mexicana promastigotes inhibit macrophage IL-12 production via TLR-4 dependent COX-2, iNOS and arginase-1 expression. Molecular Immunology 48, 1800–1808. doi: S0161-5890(11)00165-9 [pii] 10.1016/j.molimm.2011.05.013.Google Scholar
Srivastav, S., Kar, S., Chande, A. G., Mukhopadhyaya, R. and Das, P. K. (2012). Leishmania donovani exploits host deubiquitinating enzyme A20, a negative regulator of TLR signaling, to subvert host immune response. Journal of Immunology 189, 924–934. doi: jimmunol.1102845 [pii] 10.4049/jimmunol.1102845.CrossRefGoogle ScholarPubMed
Suttles, J., Milhorn, D. M., Miller, R. W., Poe, J. C., Wahl, L. M. and Stout, R. D. (1999). CD40 signaling of monocyte inflammatory cytokine synthesis through an ERK1/2-dependent pathway. A target of interleukin (il)-4 and il-10 anti-inflammatory action. Journal of Biological Chemistry 274, 5835–5842.Google Scholar
Teixeira, M. J., Fernandes, J. D., Teixeira, C. R., Andrade, B. B., Pompeu, M. L., Santana da Silva, J., Brodskyn, C. I., Barral-Netto, M. and Barral, A. (2005). Distinct Leishmania braziliensis isolates induce different paces of chemokine expression patterns. Infection and Immunology 73, 1191–1195. doi: 73/2/1191 [pii] 10.1128/IAI.73.2.1191-1195.2005.CrossRefGoogle ScholarPubMed
Tuon, F. F., Amato, V. S., Bacha, H. A., Almusawi, T., Duarte, M. I. and Amato Neto, V. (2008). Toll-like receptors and leishmaniasis. Infection and Immunology 76, 866–872. doi: IAI.01090-07 [pii] 10.1128/IAI.01090-07.CrossRefGoogle ScholarPubMed
Underhill, D. M. and Ozinsky, A. (2002). Toll-like receptors: key mediators of microbe detection. Current Opinion in Immunology 14, 103–110. doi: S0952791501003041 [pii].CrossRefGoogle ScholarPubMed
Vargas-Inchaustegui, D. A., Tai, W., Xin, L., Hogg, A. E., Corry, D. B. and Soong, L. (2009). Distinct roles for MyD88 and Toll-like receptor 2 during Leishmania braziliensis infection in mice. Infection and Immunology 77, 2948–2956. doi: IAI.00154-09 [pii] 10.1128/IAI.00154-09.CrossRefGoogle ScholarPubMed
Vitale, G., Bernardi, L., Napolitani, G., Mock, M. and Montecucco, C. (2000). Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochemical Journal 352 (Pt 3), 739–745.CrossRefGoogle ScholarPubMed
Whitaker, S. M., Colmenares, M., Pestana, K. G. and McMahon-Pratt, D. (2008). Leishmania pifanoi proteoglycolipid complex P8 induces macrophage cytokine production through Toll-like receptor 4. Infection and Immunology 76, 2149–2156. doi: IAI.01528-07 [pii] 10.1128/IAI.01528-07.CrossRefGoogle ScholarPubMed
Wilhelm, P., Ritter, U., Labbow, S., Donhauser, N., Rollinghoff, M., Bogdan, C. and Korner, H. (2001). Rapidly fatal leishmaniasis in resistant C57BL/6 mice lacking TNF. Journal of Immunology 166, 4012–4019.Google Scholar
Yang, Z., Mosser, D. M. and Zhang, X. (2007). Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. Journal of Immunology 178, 1077–1085. doi: 178/2/1077 [pii].Google Scholar