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Innate Immun. 2014 Oct;20(7):760-73. doi: 10.1177/1753425913507488. Epub 2013 Oct 31.

Diminazene aceturate (Berenil) modulates LPS induced pro-inflammatory cytokine production by inhibiting phosphorylation of MAPKs and STAT proteins.

Author information

1
Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
2
Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada uzonna@cc.umanitoba.ca.

Abstract

Although diminazene aceturate (Berenil) is widely used as a trypanolytic agent in livestock, its mechanisms of action remain poorly understood. We previously showed that Berenil treatment suppresses pro-inflammatory cytokine production by splenic and liver macrophages leading to a concomitant reduction in serum cytokine levels in mice infected with Trypanosoma congolense or challenged with LPS. Here, we investigated the molecular mechanisms through which Berenil alters pro-inflammatory cytokine production by macrophages. We show that pre-treatment of macrophages with Berenil dramatically suppressed IL-6, IL-12 and TNF-α production following LPS, CpG and Poly I:C stimulation without altering the expression of TLRs. Instead, it significantly down-regulated phosphorylation of mitogen-activated protein kinases (p38, extracellular signal-regulated kinase and c-Jun N-terminal kinases), signal transducer and activator of transcription (STAT) proteins (STAT1 and STAT3) and NF-кB p65 activity both in vitro and in vivo. Interestingly, Berenil treatment up-regulated the phosphorylation of STAT5 and the expression of suppressor of cytokine signaling 1 (SOCS1) and SOCS3, which are negative regulators of innate immune responses, including MAPKs and STATs. Collectively, these results show that Berenil down-regulates macrophage pro-inflammatory cytokine production by inhibiting key signaling pathways associated with cytokine production and suggest that this drug may be used to treat conditions caused by excessive production of inflammatory cytokines.

KEYWORDS:

Trypanosoma congolense; diminazene aceturate; immunomodulation; inflammation; intracellular signaling; proinflammatory cytokines

PMID:
24179040
DOI:
10.1177/1753425913507488
[Indexed for MEDLINE]

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