Inhibition of IL-13 and IL-13Rα2 Expression by IL-32θ in Human Monocytic Cells Requires PKCδ and STAT3 Association

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.

Molecular interactions and functions of IL-32

“…Several studies from Yoon and coworkers have shown intracellular interactions of IL-32, protein kinase C (PKC), and signal transducer and activator of transcription 3 (STAT3) 57,70,[107][108][109][110] (Fig. 2).…”

STAT3 and p53: Dual Target for Cancer Therapy

“…It forms a stable dimer to translocate into the nucleus of stimulated cells and acts as a transcription factor for numerous targeted genes. Activation of STAT3 is induced by various cytokines (interleukin (IL)-6, type I interferons) and growth factors (epidermal growth factor (EGF), platelet-derived growth factor (PDGF)) through receptors (EGFR, PDGFR) and Janus kinase (JAK) signaling pathway [ 33 , 34 , 35 , 36 , 37 , 38 ], or through oncogenic proteins (Ras, protein kinase C (PKC)) [ 39 , 40 , 41 ]. It is stringently controlled by several negative regulators, including phosphatases (Src homology region 2 (SHP2), phosphatase and tensin homolog (PTEN), CD45) [ 42 , 43 , 44 ], suppressor of cytokine signaling proteins (SOCS), mainly SOCS3 [ 45 ], and protein inhibitors of activated STAT (PIAS) proteins, particularly PIAS3 [ 46 ].…”

The Intriguing Role of Interleukin 13 in the Pathophysiology of Asthma

“…The activation of STAT6 is the primary signaling event in the response to IL-4 or IL-13 (Cao et al, 2016). In certain experimental conditions STAT1 and STAT3 can also be activated by both IL-4 and IL-13 (Wang et al, 2004; Bhattacharjee et al, 2013; Pham et al, 2019). The cytoplasmic domain of human IL-13Rα1 contains two tyrosine residues, which might serve as docking sites for STAT3 (Hershey, 2003).…”