The PDE4 inhibitor CHF6001 modulates pro-inflammatory cytokines, chemokines and Th1- and Th17-polarizing cytokines in human dendritic cells.

Abstract

Phosphodiesterase 4 (PDE4) inhibitors are used to treat autoimmune and inflammatory diseases, such as psoriasis and chronic obstructive pulmonary disease (COPD). CHF6001 is a novel, potent and selective inhaled PDE4 inhibitor in development for the treatment of COPD. When tested in vitro on human dendritic cells (DCs), CHF6001 decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CXCL8, CCL3, CXCL10 and CCL19) and of Th1- and Th17-polarizing cytokines (IL-12, IL-23 and IL-1β). In contrast to β-methasone, a reference steroid anti-inflammatory drug, CHF6001 increased the secretion of CCL22, a Th2 recruiting chemokine, and the expression of the lymph node homing receptor CCR7. Accordingly, the migration of DCs to CCR7 ligands was increased, while migration to pro-inflammatory chemokines was decreased. Of note, the action of CHF6001 was apparently mediated by a promoter-specific decrease in NF-κB p65 recruitment, independent of perturbation of LPS signalling or NF-κB nuclear translocation. Our results indicate that CHF6001 can modulate DC pro-inflammatory Th1/Th17 polarizing potential by fine tuning the transcriptional activity of the master inflammatory transcription factor NF-κB. Therefore, CHF6001 may prove useful to control Th1/Th17-polarized inflammatory diseases such as COPD.

• Authors: Veronica Gianello, Valentina Salvi, Carmen Parola, Nadia Moretto, Fabrizio Facchinetti, Maurizio Civelli, Gino Villetti, Daniela Bosisio, Silvano Sozzani
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 163 Pg. 371-380 (05 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 30851246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• tanimilast
• Anti-Infective Agents
• Cytokines
• Phosphodiesterase 4 Inhibitors
• Sulfonamides
• para-Aminobenzoates

Topics

• Anti-Infective Agents (pharmacology)
• Cells, Cultured
• Cytokines (genetics, metabolism)
• Dendritic Cells (drug effects)
• Gene Expression Regulation (drug effects)
• Humans
• Phosphodiesterase 4 Inhibitors (pharmacology)
• Sulfonamides (pharmacology)
• T-Lymphocytes (drug effects, physiology)
• para-Aminobenzoates (pharmacology)