The initial encounter of Leishmania with its host's immune system is important in the outcome of infection. Previous studies have shown that PBMCs from healthy volunteers (HV) exposed to Leishmania differ in IFN-γ production. We have expanded such observations evaluating the profile and kinetics of cytokines (IFN-γ, IL-12p70, IL-10, IL-13), chemokines (CCL5, CCL3, CCL4, CXCL10), and chemokine receptors (CCR1,CCR5, CXCR3, CCR4) in vitro L. amazonensis-stimulated of HV¿s PBMCs. HVs were divided in groups of high (HR) or low (LR) IFN-γ responders. In both groups, HR and LR, after L. amazonensis infection there was a predominance of IL-10 and IL-13 over IFN-γ production, while IL-12 was produced in similar amount. Regarding chemokines, a more striking difference was observed for CCL3 expression that was lower at 12 hours and 48 hours post infection in LR than in HR. Interestingly, a downregulation of CCR5 and a greater expression of CCR4 were found in low IFN-γ responders. These data suggest that early after L. amazonensis infection there is a cytokine milieu dominated by IL-13 and IL-10, and despite of this environment, IFN-γ is produced, supporting the complexity of the response. It is noteworthy that the pattern of immune response is mounted in first hours after Leishmania stimulation, with the definition of the differentiation of Th1 versus Th2 cells. It remains to be determined if such an in vitro difference has an in vivo counterpart in terms of susceptibility to infection.
Journal Information
Vol. 14. Issue 5.
Pages 476-482 (September - October 2010)
Vol. 14. Issue 5.
Pages 476-482 (September - October 2010)
Original article
Open Access
In vitro initial immune response against Leishmania amazonensis infection is characterized by an increased production of IL-10 and IL-13
Visits
2613
Zirlane Castelo B. Coêlho1, Maria Jania Teixeira1,
, Erika Freitas Mota1, Mércia Sindeaux Frutuoso1, João Santana da Silva2, Aldina Barral3, Manoel Barral-Netto3, Margarida Maria L. Pompeu1
Corresponding author
1 Medical School of Universidade Federal do Ceará, Rua Alexandre Baraúna, 949, Fortaleza, CE 60430-160, Brazil
2 Medical School of Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, SP 14049-900, Brazil
3 Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Rua Waldemar Falcão, 121, Salvador, BA 40296-710, Brazil
This item has received
Article information
Abstract
Keywords:
Leishmania amazonensis
interleukin-10
interleukin-13
Full text is only aviable in PDF
References
[1.]
D. McMahon-Pratt, J. Alexander.
Does the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniasis or the visceral disease?.
Immunol Rev, 201 (2004), pp. 206-224
[2.]
F.T. Silveira, R. Lainson, C.M. De Castro Gomes, M.D. Laurenti, C.E. Corbett.
Immunopathogenic competences of Leishmania (V.) braziliensis and L. (L.) amazonensis in American cutaneous leishmaniasis.
Parasite Immunol, 31 (2009), pp. 423-431
[3.]
R.O. Pinheiro, E.F. Pinto, A.B. Benedito, U.G. Lopes, B. Rossi-Bergmann.
The T-cell anergy induced by Leishmania amazonensis antigens is related with defective antigen presentation and apoptosis.
An Acad Bras Cienc, 76 (2004), pp. 519-527
[4.]
D. Sacks, N. Noben-Trauth.
The immunology of susceptibility and resistance to Leishmania major in mice.
Nat Rev Immunol, 2 (2002), pp. 845-858
[5.]
P. Tripathi, V. Singh, S. Naik.
Immune response to Leishmania: paradox rather than paradigm.
FEMS Immunol Med Microbiol, 51 (2007), pp. 229-242
[6.]
M.M.L. Pompeu, C. Brodskyn, M.J. Teixeira, et al.
Differences in gamma interferon production in vitro predict the pace of the in vitro response to Leishmania amazonensis in healthy volunteers.
Infect Immun, 69 (2001), pp. 7453-7460
[7.]
E. Bourreau, G. Prévot, R. Pradinaud, P. Launois.
Interleukin (IL)-13 is the predominant Th2 cytokine in localized cutaneous leishmaniasis lesions and renders specific CD4+ T cells unresponsive to IL-12.
J Infect Dis, 183 (2001), pp. 953-959
[8.]
M. Mahmoodi, S. Rajabalian, A. Fekri, I. Esfandiarpour.
Evaluation of in vitro production of IFN-γ, IL-10, IL-12 and IL-13 by blood cells in patients with cutaneous leishmaniasis lesions.
Iran J Allergy Asthma Immunol, 4 (2005), pp. 15-21
[9.]
P.N. Rocha, R.P. Almeida, O. Bacellar, et al.
Down-regulation of Th1 type of response in early human American cutaneous leishmaniasis.
J Infect Dis, 180 (1999), pp. 1731-1734
[10.]
K.A. Rogers, R.G. Titus.
Characterization of the early cellular immune response to Leishmania major using peripheral blood mononuclear cells from Leishmania-naive humans.
Am J Trop Med Hyg, 71 (2004), pp. 568-576
[11.]
A. Khamesipour, S. Rafati, N. Davoudi, F. Maboudi, F. Modabber.
Leishmaniasis vaccine candidates for development: a global overview.
Indian J Med Res, 123 (2006), pp. 423-438
[12.]
P. Launois, F. Tacchini-Cottier, M.P. Kieny.
Cutaneous leishmaniasis: progress towards a vaccine.
Expert Rev Vaccines, 7 (2008), pp. 1277-1287
[13.]
M.J. Teixeira, C.R. Teixeira, B.B. Andrade, M. Barral-Netto, A. Barral.
Chemokines in host-parasite interactions in leishmaniasis.
Trends Parasitol, 22 (2006), pp. 32-40
[14.]
A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, M. Locati.
The chemokine system in diverse forms of macrophage activation and polarization.
Trends Immunol, 25 (2004), pp. 677-686
[15.]
R.P. Almeida, M. Barral-Netto, A.M. De Jesus, L.A. De Freitas, E.M. Carvalho, A. Barral.
Biological behavior of Leishmania amazonensis isolated from humans with cutaneous, mucosal, or visceral leishmaniasis in BALB/C mice.
Am J Trop Med Hyg, 54 (1996), pp. 178-184
[16.]
K. Muller, G. van Zandbergen, B. Hansen, et al.
Chemokines, natural killer cells and granulocytes in the early course of Leishmania major infection in mice.
Med Microbiol Immunol, 190 (2001), pp. 73-76
[17.]
J. Alexander, F. Brombacher, H.A. McGachy, A.N. McKenzie, W. Walker, K.C. Carter.
An essential role for IL-13 in maintaining a non-healing response following Leishmania mexicana infection.
Eur J Immunol, 32 (2002), pp. 2923-2933
[18.]
D.J. Matthews, C.L. Emson, G.J. McKenzie, H.E. Jolin, J.M. Blackwell, A.N. McKenzie.
IL-13 is a susceptibility factor for Leishmania major infection.
J Immunol, 164 (2000), pp. 1458-1462
[19.]
H.W. Murray, C.W. Tsai, J. Liu, X. Ma.
Visceral Leishmania donovani infection in interleukin-13-/- mice.
Infect Immun, 74 (2006), pp. 2487-2490
[20.]
F.O. Martinez, A. Sica, A. Mantovani, M. Locati.
Macrophage activation and polarization.
Front Biosci, 13 (2008), pp. 453-461
[21.]
E. von Stebut, Y. Belkaid, T. Jakob, D.L. Sacks, M.C. Udey.
Uptake of Leishmania major amastigotes results in activation and interleukin 12 release from murine skin-derived dendritic cells: implications for the initiation of anti-Leishmania immunity.
J Exp Med, 188 (1998), pp. 1547-1552
[22.]
M.A. Marovich, M.A. McDowell, E.K. Thomas, T.B. Nutman.
IL- 12p70 production by Leishmania major-harboring human dendritic cells is a CD40/CD40 ligand-dependent process.
J Immunol, 164 (2000), pp. 5858-5865
[23.]
M. Quinones, S.K. Ahuja, P.C. Melby, L. Pate, R.L. Reddick, S.S. Ahuja.
Preformed membrane-associated stores of interleukin (IL)- 12 are a previously unrecognized source of bioactive IL-12 that is mobilized within minutes of contact with an intracellular parasite.
J Exp Med, 192 (2000), pp. 507-516
[24.]
E. von Stebut, Y. Belkaid, B.V. Nguyen, M. Cushing, D.L. Sacks, M.C. Udey.
Leishmania major-infected murine Langerhans cell-like dendritic cells from susceptible mice release IL-12 after infection and vaccinate against experimental cutaneous Leishmaniasis.
Eur J Immunol, 30 (2000), pp. 3498-3506
[25.]
S.S. Ahuja, R.L. Reddick, N. Sato, et al.
Dendritic cell (DC)-based anti-infective strategies: DCs engineered to secrete IL-12 are a potent vaccine in a murine model of an intracellular infection.
J Immunol, 163 (1999), pp. 3890-3897
[26.]
E. von Stebut, J.M. Ehrchen, Y. Belkaid, et al.
Interleukin 1alpha promotes Th1 differentiation and inhibits disease progression in Leishmania major-susceptible BALB/c mice.
J Exp Med, 198 (2003), pp. 191-199
[27.]
D. Jones, M.M. Elloso, L. Showe, D. Williams, G. Trinchieri, P. Scott.
Differential regulation of the interleukin-12 receptor during the innate immune response to Leishmania major.
Infect Immun, 66 (1998), pp. 3818-3824
[28.]
H. Himmelrich, C. Parra-Lopez, F. Tacchini-Cottier, J.A. Louis, P. Launois.
The IL-4 rapidly produced in BALB/c mice after infection with Leishmania major down-regulates IL-12 receptor beta 2-chain expression on CD4+ T cells resulting in a state of unresponsiveness to IL-12.
J Immunol, 161 (1998), pp. 6156-6163
[29.]
J. Louis, H. Himmelrich, C. Parra-Lopez, F. Tacchini-Cottier, P. Launois.
Regulation of protective immunity against Leishmania major in mice.
Curr Opin Immunol, 10 (1998), pp. 459-464
[30.]
E. Bourreau, G. Prévot, R. Pradinaud, P. Launois.
Unresponsiveness of specific T cells to IL-12 is associated with active cutaneous leishmaniasis owing to Leishmania guyanensis.
Scand J Immunol, 54 (2001), pp. 335-339
[31.]
J.K. Lacki, K.E. Wiktorowicz.
Biological properties of interleukin 10.
Postepy Hig Med Dosw, 48 (1994), pp. 363-370
[32.]
S. Nylén, D. Sacks.
Interleukin-10 and the pathogenesis of human visceral leishmaniasis.
Trends Immunol, 28 (2007), pp. 378-384
[33.]
Y. Belkaid, K.F. Hoffmann, S. Mendez, et al.
The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure.
J Exp Med, 194 (2001), pp. 1497-1506
[34.]
E. Bourreau, G. Prévot, J. Gardon, R. Pradinaud, P. Launois.
High intralesional interleukin-10 messenger RNA expression in localized cutaneous leishmaniasis is associated with unresponsiveness to treatment.
J Infect Dis, 184 (2001), pp. 1628-1630
[35.]
A. Gomes-Silva, R. de Cássia Bittar, R.N. Dos Santos, et al.
Can interferon-gamma and interleukin-10 balance be associated with severity of human Leishmania (Viannia) braziliensis infection?.
Clin Exp Immunol, 4 (2007), pp. 0-4
[36.]
M. Mohrs, C. Holscher, F. Brombacher.
Interleukin-4 receptor alpha-deficient BALB/c mice show an unimpaired T helper 2 polarization in response to Leishmania major infection.
Infect Immun, 68 (2000), pp. 1773-1780
[37.]
N. Noben-Trauth, P. Kropf, I. Muller.
Susceptibility to Leishmania major infection in interleukin-4-deficient mice.
Science, 271 (1996), pp. 987-990
[38.]
M.C. Rissoan, V. Soumelis, N. Kadowaki, et al.
Reciprocal control of T helper cell and dendritic cell differentiation.
Science, 283 (1999), pp. 1183-1186
[39.]
D. Sacks, C. Anderson.
Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in mice.
Immunol Rev, 201 (2004), pp. 225-228
[40.]
J. Alexander, K.C. Carter, N. Al-Fasi, A. Satoskar, F. Brombacher.
Endogenous IL-4 is necessary for effective drug therapy against visceral leishmaniasis.
Eur J Immunol, 30 (2000), pp. 2935-2943
[41.]
S. Stager, J. Alexander, K.C. Carter, F. Brombacher, P.M. Kay.
Both interleukin-4 (IL-4) and IL-4 receptor alpha signaling contribute to the development of hepatic granuloma with optimal anti-leishmanial activity.
Infect Immun, 71 (2003), pp. 4804-4807
[42.]
T. Biedermann, S. Zimmermann, H. Himmelrich, et al.
IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice.
Nat Immunol, 2 (2001), pp. 1054-1060
[43.]
B.G. Dorner, A. Scheffold, M.S. Rolph, et al.
MIP-1α, MIP-1β, RANTES, and ATAC/lymphotactin function together with IFN-γ as type 1 cytokines.
Proc Natl Acad Sci USA, 99 (2002), pp. 6181-6186
[44.]
J.T.L. Ness, L. Ewing, C.M. Hogaboarn, S.L. Kunkelm.
CCR4 is a key modulator of innate responses.
J Immunol, 177 (2006), pp. 7531-7539
[45.]
B. Vester, K. Muller, W. Solbach, T. Laskay.
Early gene expression of NK cell-activating chemokines in mice resistant to Leishmania major.
Infect Immun, 67 (1999), pp. 3155-3159
[46.]
H. Arase, N. Arase, T. Saito.
Interferon gamma production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking.
J Exp Med, 183 (1996), pp. 2391-2396
[47.]
J. Ji, J. Sun, L. Soong.
Impaired expression of inflammatory cytokines and chemokines at early stages of infection with Leishmania amazonensis.
Infect Immun, 71 (2003), pp. 4278-4288
[48.]
A. Varin, S. Gordon.
Alternative activation of macrophages: immune function and cellular biology.
Immunobiol, 214 (2009), pp. 630-641
[49.]
G. Weiss, C. Bogdan, M.W. Hentze.
Pathways for the regulation of macrophage iron metabolism by the anti-inflammatory cytokines IL-4 and IL-13.
J Immunol, 158 (1997), pp. 420-425
[50.]
R. Reljic, E. Stylianou, S. Balu, J.K. Ma.
Cytokine interactions that determine the outcome of mycobacterial infection of macrophages.
Cytokine, 51 (2010), pp. 42-46
[51.]
C.I. de Oliveira, M.J. Teixeira, C.R. Teixeira, et al.
A. Leishmania braziliensis isolates differing at the genome level display distinctive features in BALB/c mice.
Microbes Infect, 6 (2004), pp. 977-984
Copyright © 2010. Elsevier Editora Ltda.. All rights reserved