The involvement of TLR2 and TLR4 in cytokine and nitric oxide production in visceral leishmaniasis patients before and after treatment with anti-leishmanial drugs

PLoS One. 2015 Feb 23;10(2):e0117977. doi: 10.1371/journal.pone.0117977. eCollection 2015.

Abstract

Toll-like receptors (TLRs) have significant involvement in Leishmania infection, although little is known about the relationship between these receptors, cytokines and nitric oxide (NO) in patients with visceral leishmaniasis (VL) before or after treatment with anti-leishmanial drugs. The goal of this study was to evaluate the expression of TLR2 and TLR4 in CD3+ and CD14+ cells and the production of TNF-α, IFN-γ, IL-17, IL-10, TGF-β and NO in peripheral blood mononuclear cells (PBMCs) from VL patients pre- and post-treatment with anti-leishmanial drugs. In addition, we investigated whether these receptors were involved in the production of these cytokines and NO. In the active VL patients, increased TLR2 and TLR4 expression in lymphocytes and monocytes, increased production of TNF-α, IL-10 and TGF-β and decreased production of IFN-γ, IL-17 and NO were observed. After treatment, TLR2 and TLR4 were still expressed in lymphocytes and monocytes, the TNF-α and IL-10 levels were lower, the production of IFN-γ, IL-17 and NO was higher, and the TGF-β level remained high. Before treatment, the production of TNF-α and NO was associated with TLR2 and TLR4 expression, while IL-10 production was only associated with TLR2 expression. After treatment, both receptors were associated with the production of TNF-α, IFN-γ, IL-10 and NO, while the production of IL-17 was associated only with TLR4 expression. The results presented in this study suggest that both TLR2 and TLR4 participate in the modulation of cytokine and NO production in VL patients, contributing to the pathogenesis of VL prior to treatment and the protective immune response after treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antiprotozoal Agents / therapeutic use*
  • Cells, Cultured
  • Cytokines / biosynthesis*
  • Female
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / biosynthesis
  • Interleukin-17 / biosynthesis
  • Leishmaniasis, Visceral / blood
  • Leishmaniasis, Visceral / drug therapy*
  • Leishmaniasis, Visceral / metabolism
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Male
  • Meglumine / therapeutic use
  • Meglumine Antimoniate
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Nitric Oxide / biosynthesis*
  • Organometallic Compounds / therapeutic use
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • Transforming Growth Factor beta / biosynthesis
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Young Adult

Substances

  • Antiprotozoal Agents
  • Cytokines
  • Interleukin-17
  • Organometallic Compounds
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Nitric Oxide
  • Meglumine
  • Meglumine Antimoniate
  • Interferon-gamma

Grant support

This study was funded by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (www.fapesp.br); Scholarship: 2010/13922-5; Funding research: 2012/16289-7. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.