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J Leukoc Biol. 2015 Dec;98(6):1061-70. doi: 10.1189/jlb.3A0315-102R. Epub 2015 Aug 12.

Rhesus macaque θ-defensin RTD-1 inhibits proinflammatory cytokine secretion and gene expression by inhibiting the activation of NF-κB and MAPK pathways.

Author information

1
*Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; and Division of Rheumatology, Department of Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA tongaonk@usc.edu selsted@med.usc.edu.
2
*Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; and Division of Rheumatology, Department of Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Abstract

θ-Defensins are pleiotropic, macrocyclic peptides that are expressed uniquely in Old World monkeys. The peptides are potent, broad-spectrum microbicides that also modulate inflammatory responses in vitro and in animal models of viral infection and polymicrobial sepsis. θ-Defensins suppress proinflammatory cytokine secretion by leukocytes stimulated with diverse Toll-like receptor (TLR) ligands. Studies were performed to delineate anti-inflammatory mechanisms of rhesus θ-defensin 1 (RTD-1), the most abundant θ-defensin isoform in macaque granulocytes. RTD-1 reduced the secretion of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-8 in lipopolysaccharide (LPS)-stimulated human blood monocytes and THP-1 macrophages, and this was accompanied by inhibition of nuclear factor κB (NF-κB) activation and mitogen-activated protein kinase (MAPK) pathways. Peptide inhibition of NF-κB activation occurred following stimulation of extracellular (TLRs 1/2 and 4) and intracellular (TLR9) receptors. Although RTD-1 did not inhibit MAPK in unstimulated cells, it induced phosphorylation of Akt in otherwise untreated monocytes and THP-1 cells. In the latter, this occurred within 10 min of RTD-1 treatment and produced a sustained elevation of phosphorylated Akt (pAkt) for at least 4 h. pAkt is a negative regulator of MAPK and NF-κB activation. RTD-1 inhibited IκBα degradation and p38 MAPK phosphorylation, and stimulated Akt phosphorylation in LPS-treated human primary monocytes and THP-1 macrophages. Specific inhibition of phosphatidylinositol 3-kinase (PI3K) blocked RTD-1-stimulated Akt phosphorylation and reversed the suppression of NF-κB activation by the peptide. These studies indicate that the anti-inflammatory properties of θ-defensins are mediated by activation of the PI3K/Akt pathway and suppression of proinflammatory signals in immune-stimulated cells.

KEYWORDS:

Akt; IκBα; THP-1; TLR; monocytes

PMID:
26269197
PMCID:
PMC4661038
DOI:
10.1189/jlb.3A0315-102R
[Indexed for MEDLINE]
Free PMC Article

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