Abstract
Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator.
Highlights
Interleukin (IL) IL-13 is produced largely in Th2 lymphocytes and is implicated in the pathogenesis of allergic disorders [1,2]
Of the IL-32θ-down-regulated genes, CCL5 was previously identified as being regulated by IL-32θ, and the mechanism was proven to be through the Protein kinase C-δ (PKCδ) and signal transducer and activator of transcription 3 (STAT3) association [31]
We further explored the previous microarray profile [31] and found that IL-13Rα2 was remarkably reduced in THP-1/IL-32θ when compared to THP-1/EV (Table 1)
Summary
Interleukin (IL) IL-13 is produced largely in Th2 lymphocytes and is implicated in the pathogenesis of allergic disorders [1,2]. Another study determined that IL-13Rα2 may form a heterodimeric complex with the chitinase-like protein family member, Chi3l1, and that IL-13 can use this complex to induce TGF-beta production [8] These studies suggest that IL-13Rα2 has dual functions, including a decoy receptor function and signal transduction, depending on its relative expression and the source of IL-13. Several lines of evidence have shown that PKCδ associated with STAT3 and phosphorylated STAT3 on Ser727, leading to an inhibition of STAT3 DNA binding and transcriptional activity [25,28,29]. This kinase was found to be activated by IL-13, and inhibition of PKCδ activation greatly suppressed IL-13 induced STAT3 DNA binding [14,29] These studies support the involvement of PKCδ and STAT3 in IL-13 and IL-13Rα2 downstream signaling. Our data indicated that the inhibition of IL-32θ on STAT3 activation through PKCδ led to a decrease of STAT3 DNA binding to IL-13 and IL-13Rα2 promoters and down-regulated their expression
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