Abstract
CD4+ T-helper (Th) cell is widely recognized to be capable of influencing worm development and egg granuloma formation after schistosome infection. Interleukin (IL)-12 and IL-4 play key roles in regulation of Th cell differentiation. In the present study, we subcutaneously inoculated mice with hybridoma cells secreting monoclonal antibodies to neutralize IL-12 and IL-4 and explored the effects of IL-12 and IL-4 deficiency on the worm development and granuloma formation in mice infected with cercariae of Schistosoma japonicum. It was found that deficiency of host IL-12 and IL-4 supported normal parasite survival and fecundity. However, worm development (length and female fecundity) was significantly enhanced in anti-IL-12-treated mice. Mean length of worms in anti-IL-12-treated group was significantly greater than that of intact controls on day 28 after infection (females, 11.84 ± 1.20 mm vs. 9.45 ± 1.34; males, 9.35 ± 1.21 mm vs. 8.10 ± 0.85 mm, p < 0.05). Liver egg load per pair of worms (1,770.12 ± 470.67 vs. 806.08 ± 232.37, p < 0.05) and uterine egg load of ovigerous females (93.08 ± 27.85 vs. 46.05 ± 34.24, p < 0.05) in anti-IL-12-treated mice were significantly higher than those in intact control 28 days postinfection. But these effects diminished 42 days postinfection (p > 0.05). Granuloma size in anti-IL-12-treated mice was significantly larger than that in intact mice 42 days postinfection (398.3 ± 80.7 μm vs. 294.4 ± 72.2 μm, p < 0.05). Granuloma fibrosis dramatically intensified in anti-IL-12-treated mice but diminished in anti-IL-4-treated mice. The results suggest that IL-12 may play an impeditive role in the development of S. japonicum and in granuloma formation as well as fibrosis. IL-4 may promote granuloma formation but have no effect on worm development.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Amiri P, Locksley RM, Parslow TG, Sadick M, Rector E, Ritter D, McKerrow JH (1992) Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature 356:604–607
Cheever AW, Finkelman FD, Cox TM (1995) Anti-interleukin-4 treatment diminishes secretion of Th2 cytokines and inhibits hepatic fibrosis in murine schistosomiasis japonica. Parasite Immunol 17:103–109
Cheng YL, Song WJ, Liu WQ, Lei JH, Mo HM, Ruppel A, Li YL (2008) The effects of T cell deficiency on the development of worms and granuloma formation in mice infected with Schistosoma japonicum. Parasitol Res 102:1129–1134
Fonseca CT, Brito CF, Alves JB, Oliveira SC (2004) IL-12 enhances protective immunity in mice engendered by immunization with recombinant 14 kDa Schistosoma mansoni fatty acid-binding protein through an IFN-gamma and TNF-alpha dependent pathway. Vaccine 22(3–4):503–510
Gately MK, Desai BB, Wolitzky AG, Quinn PM, Dwyer CM, Podlaski FJ, Familletti PC, Sinigaglia F, Chizonnite R, Gubler U, Stern AS (1991) Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol 147:874–882
Germann T, Gately MK, Schoenhaut DS, Lohoff M, Mattner F, Fischer S, Jin SC, Schmitt E, Rüde E (1993) Interleukin-12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells. Eur J Immunol 23:1762–1770
Haba S, Nisonoff A (1985) Quantitation of IgE antibodies by radioimmunoassay in the presence of high concentrations of non-IgE antibodies of the same specificity. J Immunol Methods 85:39–52
Hoffmann KF, James SL, Cheever AW, Wynn TA (1999) Studies with double cytokine-deficient mice reveal that highly polarized Th1- and Th2-type cytokine and antibody responses contribute equally to vaccine-induced immunity to Schistosoma mansoni. J Immunol 163:927–938
Kayano T, Motoda R, Usui M, Ando S, Matuhasi T, Kurimoto M (1990) Growth of rat-mouse hybridoma cells in immunosuppressed hamsters. An easy and effective method to prepare monoclonal antibodies from heterohybridoma cell lines. J Immunol Methods 130:25–31
Kennel-De March A, Prin-Mathieu C, Kohler CH, Kolopp-Sarda MN, Faure GC, Béné MV (2005) Back-pack mice as a model of renal mesangial IgA dimers deposition. Int J Immunopathol Pharmacol 18:701–708
King CL, Malhotra I, Jia X (1996) Schistosoma mansoni: protective immunity in IL-4-deficient mice. Exp Parasitol 84:245–252
Kopf M, Le Gros G, Bachmann M, Lamers MC, Bluethmann H, Köhler G (1993) Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362:245–248
Kühn R, Rajewsky K, Müller W (1991) Generation and analysis of interleukin-4 deficient mice. Science 254:707–710
Moloney NA, Doenhoff MJ, Webbe G, Hinchcliffe P (1982) Studies on the host–parasite relationship of Schistosoma japonicum in normal and immunosuppressed mice. Parasite Immunol 4:431–440
Owhashi M, Kirai N, Horii Y (1997) Eosinophil chemotactic factor release from neutrophils induced by stimulation with Schistosoma japonicum eggs. Parasitol Res 83:42–46
Perussia B, Chan SH, D’Andrea A, Tsuji K, Santoli D, Pospisil M, Young D, Wolf SF, Trinchieri G (1992) Natural killer (NK) cell stimulatory factor or IL-12 has differential effects on the proliferation of TCR-alpha beta+, TCR-gamma delta + T lymphocytes, and NK cells. J Immunol 149:3495–3502
Phillips SM, DiConza JJ, Gold JA, Reid WA (1977) Schistosomiasis in the congenitally athymic (nude) mouse. I. Thymic dependency of eosinophilia, granuloma formation, and host morbidity. J Immunol 118:594–599
Ruppel A, Shi YE, Moloney NA (1990) Schistosoma mansoni and S. japonicum: comparison of levels of ultraviolet irradiation for vaccination of mice with cercariae. Parasitology 101:23–26
Schmitt E, Hoehn P, Germann T, Rüde E (1994a) Differential effects of interleukin-12 on the development of naive mouse CD4+ T cells. Eur J Immunol 24:343–347
Schmitt E, Hoehn P, Huels C, Goedert S, Palm N, Rüde E, Germann T (1994b) T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin-12 and interferon-gamma and is inhibited by transforming growth factor-beta. Eur J Immunol 24:793–798
Sher A, Coffman RL, Hieny S, Cheever AW (1990) Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity against Schistosoma mansoni in the mouse. J Immunol 145:3911–3916
Trinchieri G (1993) Interleukin-12 and its role in the generation of TH1 cells. Immunol Today 14:335–338
WHO (No authors listed) (2011) Schistosomiasis: number of people treated in 2009. Wkly Epidemiol Rec 86:73–80
Wynn TA, Eltoum I, Oswald IP, Cheever AW, Sher A (1994) Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med 179:1551–1561
Wynn TA, Reynolds A, James S, Cheever AW, Caspar P, Hieny S, Jankovic D, Strand M, Sher A (1996) IL-12 enhances vaccine-induced immunity to schistosomes by augmenting both humoral and cell-mediated immune responses against the parasite. J Immunol 157:4068–4078
Acknowledgment
This work was supported by the National Natural Foundation of China (project grant number 30771884). The research performed in this study was in compliance with the laws of China and the authors’ respective institutions.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cheng, Yl., Song, Wj., Liu, Wq. et al. The effects of interleukin (IL)-12 and IL-4 deficiency on worm development and granuloma formation in Schistosoma japonicum-infected mice. Parasitol Res 110, 287–293 (2012). https://doi.org/10.1007/s00436-011-2487-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-011-2487-0