Volume 71, Issue 5
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Interferon (IFN)- γ plays an important role during immune responses against leishmaniasis. Production of IFN-γ is regulated by interleukin (IL)-12, IL-18, and IL-15. Interferon-γ-inducible protein (IP)-10 and monokine induced by IFN-γ (Mig) are CXC chemokines, the production of which, at least in part, is IFN-γ dependent. A follow-up study of individuals infected with was undertaken in an area of Ethiopia endemic for visceral leishmaniasis (VL). Plasma levels of IFN-γ, IL-12p40, IL-18, IL-15, IP-10, and Mig were markedly elevated in symptomatic VL patients (n = 70) compared with individuals with asymptomatic infections (n = 39), malaria patients (n = 13), and healthy controls from the endemic area (n = 12). A significant decrease of IFN-γ and all mediators was observed after treatment of VL patients (n = 33). These data show that increased plasma levels of IFN-γ, as well as the mediators involved in the production and the activity of this cytokine, are characteristic of active VL in humans, and may play an important immunopathogenic role. The data also suggest that in patients with VL, the production of type 1 cytokines is not depressed, but there appears to be an unresponsiveness to the stimuli of type 1 cytokines. The underlying causes of immunologic unresponsiveness remain a subject of further investigation.


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  1. Sato N, Kuziel WA, Melby PC, Reddick RL, Kostecki V, Zhao W, Maeda N, Ahuja SK, Ahuja SS, 1999. Defects in the generation of IFN-γ are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1α-, or CCR2-deficient mice. J Immunol 163 : 5519–5525. [Google Scholar]
  2. Trinchieri G, 1998. Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv Immunol 70 : 83–243. [Google Scholar]
  3. Akira S, 2000. The role of IL-18 in innate immunity. Curr Opin Immunol 12 : 59–63. [Google Scholar]
  4. Carson WE, Ross ME, Baiocchi RA, Marien MJ, Boiani N, Grabstein K, Caligiuri MA, 1995. Endogeneous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro. J Clin Invest 96 : 2578–2582. [Google Scholar]
  5. Agostini C, Facco M, Siviero M, Carollo D, Galvan S, Cattelan AM, Zambello R, Trentin L, Semenzato G, 2000. CXC chemokines IP-10 and Mig expression and direct migration of pulmonary CD8+/CXCR3+ T cells in the lungs of patients with HIV infection and T-cell alveolitis. Am J Respir Crit Care Med 162 : 1466–1473. [Google Scholar]
  6. Jinquan T, Jing C, Jacobi HH, Reimert CM, Millner A, Quan S, Hansen JB, Dissing S, Malling HJ, Skov PS, Poulsen NK, 2000. CXCR3 expression and activation of eosinophils: role of IFN-γ-inducible protein-10 and monokine induced by IFN-γ. J Immunol 165 : 1548–1556. [Google Scholar]
  7. Gasperini S, Marchi M, Calzetti F, Laudanna C, Vicentini L, Olsen H, Murphy M, Liao F, Farber J, Cassatella MA, 1999. Gene expression and production of the monokine induced by IFN-γ (Mig), IFN-γ-inducible T cell α chemoattractant (I-TAC), and IFN-γ-inducible protein-10 (IP-10) chemokines by human neutrophils. J Immunol 162 : 4928–4937. [Google Scholar]
  8. Ribeiro-de-Jesus A, Almeida RP, Lessa H, Bacellar O, Carvalho M, 1998. Cytokine profile and pathology in human leishmaniasis. Braz J Med Biol Res 31 : 143–148. [Google Scholar]
  9. Badaro R, Jones TC, Carvalho EM, Sampaio D, Reed SG, Barral A, Teixeira R, Johnson WD Jr, 1986. New perspectives on a subclinical form of visceral leishmaniasis. J Infect Dis 154 : 1003–1011. [Google Scholar]
  10. Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM, 1989. Reciprocal expression of interferon-γ or interleukin-4 during resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 169 : 59–72. [Google Scholar]
  11. Sadick MD, Heinzel FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM, 1990. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T-cell dependent, interferon γ-independent mechanism. J Exp Med 171 : 115–127. [Google Scholar]
  12. Cenini P, Berhe N, Hailu A, McGinnes K, Frommel D, 1993. Mononuclear cell populations and cytokine levels in human visceral leishmaniasis before and after chemotherapy. J Infect Dis 168 : 986–993. [Google Scholar]
  13. Cillari E, Vitale G, Arcoleo F, D’Agostino P, Mocciaro C, Gambino G, Malta R, Stassi G, Giordano C, Milano S, Mansueto S, 1995. In vivo and in vitro cytokine profiles and mononuclear cell subsets in Sicilian patients with active visceral leishmaniasis. Cytokine 7 : 740–745. [Google Scholar]
  14. de Madeiros IM, Castelo A, Salomao R, 1998. Presence of circulating levels of interferon-γ, interleukin-10 and tumor necrosis factor-α in patients with visceral leishmaniasis. Rev Inst Med Trop Sao Paulo 40 : 31–34. [Google Scholar]
  15. Barral-Neto M, Badaro R, Barral A, Almeida RP, Santos SB, Badaro F, Pedral-Sampaio D, Carvalho EM, Falcoff E, Falcoff R, 1991. Tumor necrosis factor cachectin) in human visceral leishmaniasis. J Infect Dis 163 : 853–857. [Google Scholar]
  16. van der Poll T, Zijlstra Wd E, Mevissen M, 1995. Interleukin 6 during active visceral leishmaniasis and after treatment. Clin Immunol Immunopathol 77 : 111–114. [Google Scholar]
  17. Sundar S, Reed SG, Sharma S, Mehrotra A, Murray HW, 1997. Circulating T helper 1 (Th1) cell- and Th2 cell-associated cytokines in Indian patients with visceral leishmaniasis. Am J Trop Med Hyg 56 : 522–525. [Google Scholar]
  18. Zwingenberger K, Harms G, Pedrosa C, Omena S, Sandkamp B, Neifer S, 1990. Determinants of the immune response in visceral leishmaniasis: evidence for predominance of endogenous interleukin-4 over interferon-γ production. Clin Immunol Immunopathol 57 : 242–249. [Google Scholar]
  19. Sokal JE, 1975. Measurement of delayed skin test responses. N Engl J Med 293 : 501–502. [Google Scholar]
  20. Harith AE, Kolk AHJ, Leeuwenburg J, Muigai R, Huigen E, Jelsma T, Kager PA, 1998. Improvement of a direct agglutination test for field studies of visceral leishmaniasis. J Clin Microbiol 26 : 1321–1325. [Google Scholar]
  21. Hailu A, Berhe N, 2002. The performance of direct agglutination tests (DAT) in the diagnosis of visceral leishmaniasis among Ethiopian patients with HIV co-infection. Ann Trop Med Parasitol 96 : 25–30. [Google Scholar]
  22. Lauw FN, Simpson AJ, Prins JM, Smith MD, Kurimoto M, van Deventer SJ, Speelman P, Chaowagul W, White NL, van der Poll T, 1999. Elevated plasma concentrations of interferon (IFN)-gamma and the IFN-gamma-inducing cytokines inter-leukin (IL)-18, IL-12, and IL-15 in severe melioidosis. J Infect Dis 180 : 1878–1885. [Google Scholar]
  23. Verbon A, Juffermans N, van Deventer SJ, Speelman P, van Deutekom H, van der Poll T, 1999. Serum concentrations of cytokines in patients with active tuberculosis (TB) and after treatment. Clin Exp Immunol 115 : 110–113. [Google Scholar]
  24. Carson WE, Giri JG, Lindemann MJ, Linett ML, Ahdieh M, Paxton R, Anderson D, Eisenmann J, Grabstein K, Caligiuri MA, 1994. Interleukin (IL)15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med 180 : 1395–1403. [Google Scholar]
  25. Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K, 1998. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN- γ production. J Immunol 161 : 3400–3407. [Google Scholar]
  26. Wolday D, Berhe N, Britton S, Akuffo H, 2000. HIV-1 alters T helper cytokines, interleukin-12 and interleukin-18 responses to the protozoan parasite Leishmania donovani. AIDS 14 : 921–929. [Google Scholar]
  27. Quinnell RJ, Courtenay O, Shaw MA, Day MJ, Garcez LM, Dye C, Kaye PM, 2001. Tissue cytokine responses in canine visceral leishmaniasis. J Infect Dis 183 : 1421–1424. [Google Scholar]
  28. Waldmann TA, Tagaya Y, 1999. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu Rev Immunol 17 : 19–49. [Google Scholar]
  29. Ritter U, Moll H, Laskay T, Brocker E, Velazco O, Becker I, Gillitzer R, 1996. Differential expression of chemokines in patients with localized and diffuse cutaneous American leishmaniasis. J Infect Dis 173 : 699–709. [Google Scholar]
  30. Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR, 1998. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101 : 746–754. [Google Scholar]
  31. Balashov KE, Rottman JB, Weiner HL, Hancock WW, 1999. CCR5+ and CXCR3+ T cells are increased in multiple sclerosis and their ligands MIP-1α and IP-10 are expressed in de-myelinating brain lesions. Proc Natl Acad Sci USA 96 : 6873–6878. [Google Scholar]
  32. Agostini C, Cassatella M, Zambello R, Trentin L, Gasperini S, Perin A, Piazza F, Siviero M, Facco M, Dziejman M, Chilosi M, Qin S, Luster AD, Semenzato G, 1998. Involvement of the IP-10 chemokine in sarcoid granulomatous reactions. J Immunol 161 : 6413–6420. [Google Scholar]
  33. Musso T, Calosso L, Zucca M, Millesimo M, Ravarino D, Giovarelli M, Malavasi F, Ponzi AN, Paus R, Bulfone-Paus S, 1999. Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma up-regulated interleukin-15. Blood 93 : 3531–3539. [Google Scholar]
  34. Farber JM, 1997. Mig and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol 61 : 246–257. [Google Scholar]
  35. Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozanni S, Allavena P, Gray PA, Mantovani S, Sinigaglia S, 1998. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187 : 129–134. [Google Scholar]
  36. Cotterell SE, Engwerda CR, Kaye PM, 1999. Leishmania donovani infection initiates T cell-independent chemokine responses, which are subsequently amplified in a T-cell dependent manner. Eur J Immunol 29 : 203–214. [Google Scholar]
  37. Kaplan G, Luster AD, Hancock G, Cohn ZA, 1987. The expression of a gamma interferon-induced protein (IP-10) in delayed immune responses in human skin. J Exp Med 166 : 1098–1108. [Google Scholar]
  38. Hussain S, Zwilling BS, Lafuse WP, 1999. Mycobacterium avium infection of mouse macrophages inhibit IFN-gamma Janus kinase-STAT signaling and gene induction by down-regulation of the IFN-gamma receptor. J Immunol 163 : 2041–2048. [Google Scholar]
  39. Nandan D, Lo R, Reiner NE, 1999. Activation of phosphotyrosine phophatase activity attenuates mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide synthase expression in macrophages infected with Leishmania donovani. Infect Immun 67 : 4055–4063. [Google Scholar]
  40. Nandan D, Yi T, Lopez M, Lai C, Reiner NE, 2002. Leishmania EF-1alpha activates the Src homology 2 domain containing tyrosine phosphatase SHP-1 leading to macrophage deactivation. J Biol Chem 277 : 50190–50197. [Google Scholar]
  41. Bhattacharyya S, Ghosh S, Jhonson PL, Bhattacharya SK, Majumdar S, 2001. Immunomodulatory role of interleukin-10 in visceral leishmaniasis: defective activation of protein kinase C-mediated signal transduction events. Infect Immun 69 : 1499–1507. [Google Scholar]
  42. Xaus J, Mirabet M, Lloberas J, Soler C, Lluis C, Franco R, Celada A, 1999. IFN- gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. J Immunol 162 : 3607–3614. [Google Scholar]
  43. Hailu A, Menon JN, Berhe N, Gedamu L, Hassard TH, Kager PA, Olobo J, Bretscher PA, 2001. Distinct immunity in visceral leishmaniasis patients from that in sub-clinically infected and drug-cured people: implications for the mechanism underlying drug-cure. J Infect Dis 184 : 112–115. [Google Scholar]

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  • Received : 22 Jan 2004
  • Accepted : 09 Jun 2004

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