Rhesus macaque θ-defensin RTD-1 inhibits proinflammatory cytokine secretion and gene expression by inhibiting the activation of NF-κB and MAPK pathways
Identifieur interne : 000484 ( Ncbi/Merge ); précédent : 000483; suivant : 000485Rhesus macaque θ-defensin RTD-1 inhibits proinflammatory cytokine secretion and gene expression by inhibiting the activation of NF-κB and MAPK pathways
Auteurs : Prasad Tongaonkar ; Katie K. Trinh ; Justin B. Schaal ; Dat Tran ; Percio S. Gulko ; André J. Ouellette ; Michael E. SelstedSource :
- Journal of Leukocyte Biology [ 0741-5400 ] ; 2015.
Abstract
The anti-inflammatory effects of θ-defensin RTD-1 are mediated by cell signaling pathways that down-regulate expression of pro-inflammatory cytokines.
Url:
DOI: 10.1189/jlb.3A0315-102R
PubMed: 26269197
PubMed Central: 4661038
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PMC:4661038Le document en format XML
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<author><name sortKey="Tongaonkar, Prasad" sort="Tongaonkar, Prasad" uniqKey="Tongaonkar P" first="Prasad" last="Tongaonkar">Prasad Tongaonkar</name>
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<front><div type="abstract" xml:lang="en"><p>The anti-inflammatory effects of θ-defensin RTD-1 are mediated by cell signaling pathways that down-regulate expression of pro-inflammatory cytokines.</p>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Leukoc Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Leukoc. Biol</journal-id>
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<article-categories><subj-group subj-group-type="heading"><subject>Inflammation, Extracellular Mediators, & Effector Molecules</subject>
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<title-group><article-title>Rhesus macaque θ-defensin RTD-1 inhibits proinflammatory cytokine secretion and gene expression by inhibiting the activation of NF-κB and MAPK pathways</article-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Tongaonkar</surname>
<given-names>Prasad</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
<xref ref-type="corresp" rid="cor1"><sup>1</sup>
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<contrib contrib-type="author"><name><surname>Trinh</surname>
<given-names>Katie K.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schaal</surname>
<given-names>Justin B.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>Tran</surname>
<given-names>Dat</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>Gulko</surname>
<given-names>Percio S.</given-names>
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<xref ref-type="aff" rid="aff2"><sup>†</sup>
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<contrib contrib-type="author"><name><surname>Ouellette</surname>
<given-names>André J.</given-names>
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<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>Selsted</surname>
<given-names>Michael E.</given-names>
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<xref ref-type="aff" rid="aff1">*</xref>
<xref ref-type="corresp" rid="cor1"><sup>1</sup>
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<aff><target id="aff1" target-type="aff">*</target>
Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; and<target id="aff2" target-type="aff"><sup>†</sup>
</target>
Division of Rheumatology, Department of Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA</aff>
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<author-notes><corresp id="cor1"><label>1</label>
Correspondence: Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, 7504 NRT, 1450 Biggy St., Los Angeles, CA 90033, USA. E-mail: <email>tongaonk@usc.edu</email>
(P.T.) and <email>selsted@med.usc.edu</email>
(M.E.S.)</corresp>
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<volume>98</volume>
<issue>6</issue>
<fpage>1061</fpage>
<lpage>1070</lpage>
<history><date date-type="received"><day>10</day>
<month>3</month>
<year>2015</year>
</date>
<date date-type="rev-recd"><day>18</day>
<month>6</month>
<year>2015</year>
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<date date-type="accepted"><day>12</day>
<month>7</month>
<year>2015</year>
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<permissions><copyright-statement>© Society for Leukocyte Biology</copyright-statement>
<copyright-year>2015</copyright-year>
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<abstract abstract-type="precis"><p>The anti-inflammatory effects of θ-defensin RTD-1 are mediated by cell signaling pathways that down-regulate expression of pro-inflammatory cytokines.</p>
</abstract>
<abstract><p>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.</p>
</abstract>
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<name sortKey="Ouellette, Andre J" sort="Ouellette, Andre J" uniqKey="Ouellette A" first="André J." last="Ouellette">André J. Ouellette</name>
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<name sortKey="Selsted, Michael E" sort="Selsted, Michael E" uniqKey="Selsted M" first="Michael E." last="Selsted">Michael E. Selsted</name>
<name sortKey="Tongaonkar, Prasad" sort="Tongaonkar, Prasad" uniqKey="Tongaonkar P" first="Prasad" last="Tongaonkar">Prasad Tongaonkar</name>
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