Pellino1 promoted inflammation in lung injury model of sepsis by TRAF6/ NF-κB signal pathway

Abstract

Background This study was designed to investigate the role of Pellino1 in lung injury model of sepsis and its anti-inflammation mechanism. Method: C57BL/6 male mice (6–7 weeks old) and Pellino1−/− male mice were subjected to laparotomy followed by extracorporeal cecum mobilization and ligation. THP-1 cells were treated with 500 ng/ml of LPS for 4 h. Both mRNA and protein expression of Pellino1 was increased at time dependence in lung tissue of lung injury model of sepsis mice. Knockout of Pellino1 attenuated lung injury and inhibited inflammation of sepsis mice. While Pellino1 protein enhanced lung injury and increased inflammation of sepsis mice. Pellino1 promoted inflammation in in vitro model of lung injury by TRAF6/ NF-κB signal pathway. Result TRAF6 inhibitor attenuated the effects of Pellino1 on inflammation and lung injury in mice of sepsis. Similarly, NF-κB inhibitor also suppressed the effects of Pellino1 on inflammation and lung injury in mice of sepsis. The activation of TRAF6 or induction of NF-κB attenuated the effects of Pellino1 on inflammation in in vitro model of sepsis. The inhibition of TRAF6 or suppression of NF-κB reduced the effects of Pellino1 on inflammation in in vitro model of sepsis. Conclusions These results suggested that Pellino1 promoted inflammation in lung injury model of sepsis by TRAF6/ NF-κB signal pathway.

The Emerging Roles of Pellino Family in Pattern Recognition Receptor Signaling

“…Although mediated by LPS, the Pellino family plays a different role in endotoxin tolerance in macrophages. Endotoxin tolerance abrogated Pellino1 induction by LPS in macrophages (69,71,72) but an enhanced expression of Pellino3 (79). Elevated transcription of TNFa and IL-6 driven by TLR2/4 and also increased expression of C-C motif chemokine ligand 5 (CCL5) driven by TLR4 were observed in Pellino3-deficient human myeloid leukemia mononuclear cells (THP-1) in response to TLR agonists (79).…”

“…Pellino1 positively regulates the production of inflammatory factors in MyD88-dependent TLR signaling (69,70) as MyD88 deficiency hindered the expression of Pellino1, NF-kB, IL-1b, IL-6, Beclin-1, and cyclooxygenase-2 (COX-2) in a cerebral ischemia/reperfusion (I/R) mouse model (70). Pellino1 also positively regulates the MyD88-dependent pathway by promoting K63 linked polyubiquitination of IRAK1, TBK1, TRAF6, and TAK1 to active the MAPK and NF-kB signaling pathways via TLR2 and TLR4 pathway (69,71). Upon LPS stimulation, the expression of Pellino1 is upregulated (69,71,72), possibly by increasing levels of p65 and phosphorylated IKKa/b in microglia (73).…”

“…Pellino1 also positively regulates the MyD88-dependent pathway by promoting K63 linked polyubiquitination of IRAK1, TBK1, TRAF6, and TAK1 to active the MAPK and NF-kB signaling pathways via TLR2 and TLR4 pathway (69,71). Upon LPS stimulation, the expression of Pellino1 is upregulated (69,71,72), possibly by increasing levels of p65 and phosphorylated IKKa/b in microglia (73). Upregulated Pellino1 activates microglia and enhances NF-kB production, MAPK phosphorylation, and proinflammatory cytokines in LPS-induced TLR4 signaling by increasing TRAF6 K63-linked ubiquitination (64)(65)(66).…”

PEP-sNASP Peptide Alleviates LPS-Induced Acute Lung Injury Through the TLR4/TRAF6 Axis

“…TRAF6 is a key adaptor for TLR4/NF-κB signaling in regulating innate and adaptive immunity ( 43 , 44 ). Increasing evidence indicates that the TLR4/TRAF6 pathway is considered to be involved in the process of inflammation-related ALI ( 45 – 47 ). For example, Ding et al and Liu et al both demonstrated that the inhibition of TRAF6 alleviated the severity of inflammation and lung injury in an ALI mouse model ( 45 , 47 ).…”

“…Increasing evidence indicates that the TLR4/TRAF6 pathway is considered to be involved in the process of inflammation-related ALI ( 45 – 47 ). For example, Ding et al and Liu et al both demonstrated that the inhibition of TRAF6 alleviated the severity of inflammation and lung injury in an ALI mouse model ( 45 , 47 ). Inhibition of TRAF6 ubiquitination can attenuate TRAF6-mediated NF-κB activation and proinflammatory cytokine expressions ( 45 , 46 , 48 ).…”