Inflammatory cytokines IL-32 and IL-17 have common signaling intermediates despite differential dependence on TNF-receptor 1

J Immunol. 2011 Jun 15;186(12):7127-35. doi: 10.4049/jimmunol.1002306. Epub 2011 May 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cytokines / metabolism*
  • Death-Associated Protein Kinases
  • Humans
  • Inflammation Mediators / metabolism*
  • Interleukin-17 / metabolism*
  • Interleukins / metabolism*
  • Receptors, Tumor Necrosis Factor / immunology*
  • Signal Transduction
  • p300-CBP Transcription Factors


  • Apoptosis Regulatory Proteins
  • Cytokines
  • IL32 protein, human
  • Inflammation Mediators
  • Interleukin-17
  • Interleukins
  • Receptors, Tumor Necrosis Factor
  • p300-CBP Transcription Factors
  • DAPK1 protein, human
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases

Associated data

  • GEO/GSE28649