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

Abstract

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 10 6 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 diseasepromoting effect in pulmonary paracoccidioidomycosis depending on the genetic background of the host.

Pulmonary immune responses induced in BALB/c mice by Paracoccidioides brasiliensis conidia

“…In the chronic phase of the disease, susceptible animals presented a transitory secretion of IL-2, and IL-4, and in the pulmonary infection, IL-4, IL-5 and IL-10 were preferentially detected in lung cells' washings of susceptible animals [62]. In addition, Arruda et al [131], demonstrated a dual role for IL-4 in pulmonary paracoccidioidomycosis, as endogenous IL-4 could induce protection or exacerbation of the disease depending on the host genetic pattern. Other study showed that IL-12 protects mice against disseminated infection caused by P. brasiliensis, but enhances pulmonary inflammation [132].…”

Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells

“…Importantly, the early administration of IL-12 does not reverse the susceptibility of B10.A mice but induces an excessive pulmonary inflammation (30). IL-4 depletion, instead of abolishing the susceptibility of B10.A mice, induces a more severe disease (31). Moreover, early in infection, higher levels of IFN-␥ were found in the lungs of B10.A but not A/J mice (32).…”

Intercellular Adhesion Molecule-1 Is Required for the Early Formation of Granulomas and Participates in the Resistance of Mice to the Infection with the Fungus Paracoccidioides brasiliensis

“…Indeed, IL-4 is related with susceptibility and deficient formation of granulomas in P. brasiliensis-infected mice. 41,42 Altogether, these findings suggest that the expression of ICAM-1 in the lungs of mice infected with P. brasiliensis contributes not only to the recruitment and adhesion of circulating T cells but also to the formation and organization of granulomas and with the adequate balance of cytokine production. Together these events orchestrate the generation of effector immune responses and the host defenses responsible for preventing the fungus to escape and disseminate.…”