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Infection and Immunity, July 2004, p. 3932-3940, Vol. 72, No. 7
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.7.3932-3940.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dual Role of Interleukin-4 (IL-4) in Pulmonary Paracoccidioidomycosis: Endogenous IL-4 Can Induce Protection or Exacerbation of Disease Depending on the Host Genetic Pattern

Celina Arruda,1 Rita C. Valente-Ferreira,1 Adriana Pina,1 Suely S. Kashino,1 Raquel A. Fazioli,1 Celidéia A. C. Vaz,1 Marcello F. Franco,2 Alexandre C. Keller,1 and Vera L. G. Calich1*

Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo,1 Departamento de Patologia, Faculdade de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil2

Received 13 October 2003/ Returned for modification 10 December 2003/ Accepted 25 March 2004

Resistance to paracoccidioidomycosis, the most important endemic mycosis in Latin America, is thought to be primarily mediated by cellular immunity and the production of gamma interferon. To assess the role of interleukin-4 (IL-4), a Th2 cytokine, pulmonary paracoccidioidomycosis in IL-4-depleted susceptible (B10.A) and intermediate (C57BL/6) mice was studied. Two different protocols were used to neutralize endogenous IL-4 in B10.A mice: 1 mg of anti-IL-4 monoclonal antibody (MAb)/week and 8 mg 1 day before intratracheal infection with 106 Paracoccidioides brasiliensis yeast cells. Unexpectedly, both protocols enhanced pulmonary infection but did not alter the levels of pulmonary cytokines and specific antibodies. Since in a previous work it was verified that C57BL/6 mice genetically deficient in IL-4 were more resistant to P. brasiliensis infection, we also investigated the effect of IL-4 depletion in this mouse strain. Treatment with the MAb at 1 mg/week led to less severe pulmonary disease associated with impaired synthesis of Th2 cytokines in the lungs and liver of control C57BL/6 mice. Conversely, in IL-4-depleted C57BL/6 mice, increased levels of tumor necrosis factor alpha and IL-12 were found in the lungs and liver, respectively. In addition, higher levels of immunoglobulin G2a (IgG2a) and lower levels of IgG1 antibodies were produced by IL-4-depleted mice than by control mice. Lung pathologic findings were equivalent in IL-4-depleted and untreated B10.A mice. In IL-4-depleted C57BL/6 mice, however, smaller and well-organized granulomas replaced the more extensive lesions that developed in untreated mice. These results clearly showed that IL-4 can have a protective or a disease-promoting effect in pulmonary paracoccidioidomycosis depending on the genetic background of the host.

* Corresponding author. Mailing address: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1730, CEP 05508-900, São Paulo, São Paulo, Brazil. Phone: 55-11-30917397. Fax: 55-11-30917224. E-mail: vlcalich{at}icb.usp.br.

Editor: S. H. E. Kaufmann

Infection and Immunity, July 2004, p. 3932-3940, Vol. 72, No. 7
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.7.3932-3940.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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