Inflammatory Cytokines IL-32 and IL-17 Have Common Signaling Intermediates despite Differential Dependence on TNF-Receptor 1

Abstract

Cytokines IL-32 and IL-17 are emerging as critical players in the pathophysiology of immune-mediated chronic inflammatory diseases. It has been speculated that the molecular mechanisms governing IL-32– and IL-17–mediated cellular responses are differentially dependent on the TNF pathway. In this study, kinome analysis demonstrated that following stimulation with cytokine IL-32, but not IL-17, there was increased phosphorylation of a peptide target corresponding to TNF-R1. Consistent with this observation, blocking TNF-R1 resulted in a suppression of IL-32–induced downstream responses, indicating that IL-32–mediated activity may be dependent on TNF-R1. In contrast, blocking TNF-R1 did not affect IL-17–induced downstream responses. Kinome analysis also implicated p300 (transcriptional coactivator) and death-associated protein kinase-1 (DAPK-1) as signaling intermediates for both IL-32 and IL-17. Phosphorylation of p300 and DAPK-1 upon stimulation with either IL-32 or IL-17 was confirmed by immunoblots. The presence of common targets was supported by results demonstrating similar downstream responses induced in the presence of IL-32 and IL-17, such as transcriptional responses and the direct activation of NF-κB. Furthermore, knockdown of p300 and DAPK-1 altered downstream responses induced by IL-32 and IL-17, and impacted certain cellular responses induced by TNF-α and IL-1β. We hypothesize that p300 and DAPK-1 represent nodes where the inflammatory networks of IL-32 and IL-17 overlap, and that these proteins would affect both TNF-R1–dependent and –independent pathways. Therefore, p300 and DAPK-1 are viable potential therapeutic targets for chronic inflammatory diseases.

MicroRNA-26b inhibits cell proliferation and cytokine secretion in human RASF cells via the Wnt/GSK-3β/β-catenin pathway

“…Although the exact mechanism of this effect need to be further investigated, we believe that miR-26b is intimately involved in RA progression and miR-26b based strategies have the potential to be highly effective against synovium inflammation in RA, consistent with earlier observations by Turner-Brannen et al [50]. Our study is also supported by Tomoyuki Nakasa et al, who presented convincing results that NF-κB activity is critical for the initiation and maintenance of chronic inflammation in RA synovial tissue [15].…”

IL-32θ downregulates CCL5 expression through its interaction with PKCδ and STAT3

“…With this discovery, we investigated the functional role of IL-32θ in the immune response. Despite the conflicting data pertaining to the role of IL-32 in regulating the inflammatory response [2][3][4][5], this study revealed that IL-32θ can regulate CCL5 expression in human myelomonocytic THP-1 cells. Although many reports have emphasized the importance of CCL5 in the development of disease [58,61,62,65], few studies have investigated the mechanisms mediating the effects of IL-32 on CCL5 expression.…”

“…The function of interleukin (IL)-32, formerly named natural killer cell transcript 4 [1], has been previously described in several studies [2][3][4][5][6][7]. The protein sequence of IL-32 is distinct in that it is not homologous with any other cytokines [8].…”

Ultrashort Cationic Lipopeptides and Lipopeptoids Selectively Induce Cytokine Production in Macrophages

“…The cells were rested for twenty-four hours, then exposed to the amphiphiles of interest for twenty-four hours. Cell free TC supernatants were monitored for the production of chemokines Groα and IL-8 by ELISA as previously described [31], [34]. The constitutive background level of chemokine Groα was 6.6±1.8 pg/ml, and that of IL-8 was 1.7±0.16 ng/ml.…”