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The PDE4 inhibitor CHF6001 modulates pro-inflammatory cytokines, chemokines and Th1- and Th17-polarizing cytokines in human dendritic cells.
Biochem Pharmacol 2019; 163:371-380BP

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+Show Affiliations

Department of Molecular and Translational Medicine, University of Brescia, Italy.Department of Molecular and Translational Medicine, University of Brescia, Italy.Department of Molecular and Translational Medicine, University of Brescia, Italy.Chiesi Farmaceutici S.p.A., Corporate Pre-Clinical R&D, Largo F. Belloli 11/A, Parma 43122, Italy.Chiesi Farmaceutici S.p.A., Corporate Pre-Clinical R&D, Largo F. Belloli 11/A, Parma 43122, Italy.Chiesi Farmaceutici S.p.A., Corporate Pre-Clinical R&D, Largo F. Belloli 11/A, Parma 43122, Italy.Chiesi Farmaceutici S.p.A., Corporate Pre-Clinical R&D, Largo F. Belloli 11/A, Parma 43122, Italy.Department of Molecular and Translational Medicine, University of Brescia, Italy.Department of Molecular and Translational Medicine, University of Brescia, Italy. Electronic address: silvano.sozzani@unibs.it.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30851246

Citation

Gianello, Veronica, et al. "The PDE4 Inhibitor CHF6001 Modulates Pro-inflammatory Cytokines, Chemokines and Th1- and Th17-polarizing Cytokines in Human Dendritic Cells." Biochemical Pharmacology, vol. 163, 2019, pp. 371-380.
Gianello V, Salvi V, Parola C, et al. The PDE4 inhibitor CHF6001 modulates pro-inflammatory cytokines, chemokines and Th1- and Th17-polarizing cytokines in human dendritic cells. Biochem Pharmacol. 2019;163:371-380.
Gianello, V., Salvi, V., Parola, C., Moretto, N., Facchinetti, F., Civelli, M., ... Sozzani, S. (2019). The PDE4 inhibitor CHF6001 modulates pro-inflammatory cytokines, chemokines and Th1- and Th17-polarizing cytokines in human dendritic cells. Biochemical Pharmacology, 163, pp. 371-380. doi:10.1016/j.bcp.2019.03.006.
Gianello V, et al. The PDE4 Inhibitor CHF6001 Modulates Pro-inflammatory Cytokines, Chemokines and Th1- and Th17-polarizing Cytokines in Human Dendritic Cells. Biochem Pharmacol. 2019;163:371-380. PubMed PMID: 30851246.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The PDE4 inhibitor CHF6001 modulates pro-inflammatory cytokines, chemokines and Th1- and Th17-polarizing cytokines in human dendritic cells. AU - Gianello,Veronica, AU - Salvi,Valentina, AU - Parola,Carmen, AU - Moretto,Nadia, AU - Facchinetti,Fabrizio, AU - Civelli,Maurizio, AU - Villetti,Gino, AU - Bosisio,Daniela, AU - Sozzani,Silvano, Y1 - 2019/03/06/ PY - 2019/01/22/received PY - 2019/03/04/accepted PY - 2019/3/10/pubmed PY - 2019/3/10/medline PY - 2019/3/10/entrez KW - Myeloid DCs KW - NF-κB KW - Phosphodiesterase 4 inhibitors KW - Plasmacytoid DCs SP - 371 EP - 380 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 163 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/30851246/The_PDE4_inhibitor_CHF6001_modulates_pro_inflammatory_cytokines_chemokines_and_Th1__and_Th17_polarizing_cytokines_in_human_dendritic_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(19)30092-9 DB - PRIME DP - Unbound Medicine ER -