Abstract
Polo-like kinases (PLKs) have been reported to be essential components of anti-viral pathways. However, the role of PLKs in the production of pro-inflammatory cytokines induced by TLR activation is uncertain. We report here that monocytic THP-1 cells expressed PLK1, PLK2, PLK3 and PLK4. When THP-1 cells were treated with GW843682X, an inhibitor of PLK1 and PLK3, the results showed that GW843682X down-regulated Pam3CSK4- and LPS-induced TNF-α at both the gene and protein levels. GW843682X did not impact Pam3CSK4-induced IL-1β and IL-8 or LPS-induced IL-1β, but it down-regulated LPS-induced IL-8 significantly. Moreover, western blot results showed that TLRs activated PLK1, and PLK1 inhibition by RNA interference down-regulated Pam3CSK4-induced TNF-α production, suggesting the involvement of PLK1 in TNF-α up-regulation. In addition, GW843682X treatment for 12 to 24 h induced cell death and down-regulated MyD88, but neither of these roles contributed to the down-regulation of TNF-α, as TNF-α gene expression was up-regulated at 1 h. Furthermore, GW843682X inhibited Pam3CSK4-induced activation of ERK and NF-κB, which contributed to Pam3CSK4-induced up-regulation of TNF-α. GW843682X also inhibited LPS-induced activation of ERK, p38 and NF-κB, which contributed to LPS-induced up-regulation of TNF-α. Taken together, these results suggested that PLK1 is involved in TLR2- and TLR4-induced inflammation, and GW843682X may be valuable for the regulation of the inflammatory response.
Highlights
Toll-like receptors (TLRs) are type I transmembrane proteins, and they function as pattern recognition receptors (PRRs) to detect the conserved structures of pathogens known as pathogen-associated molecular patterns (PAMPs) [1,2]
When THP-1 cells were treated with GW843682X, an inhibitor of Polo-Like Kinase 1 (PLK1) and PLK3, the Quantitative real time RT-PCR (qRT-PCR) results showed that GW843682X did not affect the gene expression of PLK1, PLK2, PLK3, or PLK4 (Figure 1C)
Suggesting that PLK1 was involved in the production of TNF-α induced by TLR activation
Summary
Toll-like receptors (TLRs) are type I transmembrane proteins, and they function as pattern recognition receptors (PRRs) to detect the conserved structures of pathogens known as pathogen-associated molecular patterns (PAMPs) [1,2]. The activation of TLRs elicits multiple signaling events, leading to the induction of pro-inflammatory cytokines and resulting in the activation of the innate immune response. The dimerization of TLR3 and TLR4 recruits the TIR-domain-containing adaptor protein-inducing IFN-β (TRIF), which associates with TRAF3, leading to the activation of NFκB and interferon regulatory factor 3 (IRF3) and the production of type I interferons [5]. TLR activation induces multiple pathways that mediate proinflammatory responses. The inhibition of glycogen synthase kinase 3 signaling shifted the TLR-mediated proinflammatory response to the anti-inflammatory response via activation of the CREB pathway [7,8]. Protein kinases D1 and D2 have been reported to be involved in chemokine production induced by TLR2, 4, and 5 [11]
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