title: Impaired macrophage responses may contribute to exacerbation of blood-stage Plasmodium chabaudi chabaudi malaria in interleukin-12-deficient mice.
abstract: Aiming to clarify the role of endogenous interleukin-12 (IL-12) in protective immunity against blood stages of Plasmodium chabaudi chabaudi (AS), we evaluated the course of infection in IL-12p40 gene knockout (IL-12p40KO) and wild-type (WT) C57BL/6 mice, focusing (1) on the ability of T cells to develop adequate type 1 responses and (2) on the potentiality of macrophages to respond to parasites, interferon-gamma (IFN-gamma), or both. We observed that IL-12p40KO mice develop significantly higher parasitemias during the acute infection, although mice from both groups clear the parasites within a month and similarly eliminate a secondary challenge. Thus, fully protective immunity to P. c. chabaudi can be generated in the absence of IL-12. However, this cytokine may promote parasite control during the early phase of infection. The increased acute parasitemia of IL-12p40KO mice was associated with both impaired IFN-gamma and nitric oxide (NO) response by spleen cells. Because stimulation with recombinant IFN-gamma (rIFN-gamma) failed to improve the NO response in IL-12p40KO macrophages, we investigated whether these cells have an intrinsic defect. Analysis of peritoneal macrophages revealed that IL-12p40KO cells produce higher levels of transforming growth factor-beta1 (TGF-beta1) compared with WT cells and respond to infected erythrocytes or rIFN-gamma by releasing little NO. Moreover, IL-12p40KO macrophages had a severely impaired ability to internalize opsonized infected erythrocytes, suggesting that the low effector profile assumed by these cells may compromise antibody-mediated immunity. Taken together, our results support the idea that the absence of IL-12p40 not only affects IFN-gamma production but also has deep consequences in macrophage effector functions that may contribute to exacerbation of the early phase of P. c. chabaudi malaria.
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Av. Prof Lineu Prestes 1730, Universidade de São Paulo, São Paulo, SP Brazil CEP-05508-900.
authors.forename: Karina R B
authors.initials: KR
authors.lastname: Bastos
authors.forename: Renato
authors.initials: R
authors.lastname: Barboza
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Elias
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Sardinha
authors.forename: Marcos G
authors.initials: MG
authors.lastname: Grisotto
authors.forename: Cláudio R F
authors.initials: CR
authors.lastname: Marinho
authors.forename: Gustavo P
authors.initials: GP
authors.lastname: Amarante-Mendes
authors.forename: José M
authors.initials: JM
authors.lastname: Alvarez
authors.forename: Maria Regina D'Império
authors.initials: MR
authors.lastname: Lima
mesh_terms: D000818:Animals; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008288:Malaria / Q000097:blood* / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D018512:Parasitemia / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D010587:Phagocytosis; D011994:Recombinant Proteins; D013154:Spleen / Q000276:immunology; D013997:Time Factors
chemical_list: D011994:Recombinant Proteins; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma