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  • Title: Diminazene aceturate (Berenil) modulates LPS induced pro-inflammatory cytokine production by inhibiting phosphorylation of MAPKs and STAT proteins.
    Author: Kuriakose S, Muleme H, Onyilagha C, Okeke E, Uzonna JE.
    Journal: Innate Immun; 2014 Oct; 20(7):760-73. PubMed ID: 24179040.
    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.
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