PMID- 31641194 OWN - NLM STAT- MEDLINE DCOM- 20201028 LR - 20210110 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 9 IP - 1 DP - 2019 Oct 22 TI - The anti-inflammatory agent bindarit acts as a modulator of fatty acid-binding protein 4 in human monocytic cells. PG - 15155 LID - 10.1038/s41598-019-51691-y [doi] LID - 15155 AB - We investigated the cellular and molecular mechanisms by which bindarit, a small indazolic derivative with prominent anti-inflammatory effects, exerts its immunoregulatory activity in lipopolysaccharide (LPS) stimulated human monocytic cells. We found that bindarit differentially regulates the release of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), enhancing the release of IL-8 and reducing that of MCP-1. These effects specifically required a functional interaction between bindarit and fatty acid binding protein 4 (FABP4), a lipid chaperone that couples intracellular lipid mediators to their biological targets and signaling pathways. We further demonstrated that bindarit can directly interact with FABP4 by increasing its expression and nuclear localization, thus impacting on peroxisome proliferator-activated receptor gamma (PPARgamma) and LPS-dependent kinase signaling. Taken together, these findings suggest a potential key-role of FABP4 in the immunomodulatory activity of bindarit, and extend the spectrum of its possible therapeutic applications to FABP4 modulation. FAU - Oddi, Sergio AU - Oddi S AUID- ORCID: 0000-0002-6217-698X AD - Faculty of Veterinary Medicine, University of Teramo, Teramo, 64100, Italy. soddi@unite.it. AD - European Center for Brain Research (CERC)/Santa Lucia Foundation IRCCS, Rome, 00143, Italy. soddi@unite.it. FAU - Scipioni, Lucia AU - Scipioni L AD - European Center for Brain Research (CERC)/Santa Lucia Foundation IRCCS, Rome, 00143, Italy. FAU - Totaro, Antonio AU - Totaro A AD - European Center for Brain Research (CERC)/Santa Lucia Foundation IRCCS, Rome, 00143, Italy. FAU - Angelucci, Clotilde AU - Angelucci C AD - Faculty of Veterinary Medicine, University of Teramo, Teramo, 64100, Italy. FAU - Dufrusine, Beatrice AU - Dufrusine B AD - Faculty of Veterinary Medicine, University of Teramo, Teramo, 64100, Italy. FAU - Sabatucci, Annalaura AU - Sabatucci A AD - Faculty of Veterinary Medicine, University of Teramo, Teramo, 64100, Italy. FAU - Tortolani, Daniel AU - Tortolani D AD - Faculty of Veterinary Medicine, University of Teramo, Teramo, 64100, Italy. FAU - Coletta, Isabella AU - Coletta I AD - Angelini RR&D (Research, Regulatory & Development), Angelini S.p.A., Rome, 00181, Italy. FAU - Alisi, Maria Alessandra AU - Alisi MA AD - Angelini RR&D (Research, Regulatory & Development), Angelini S.p.A., Rome, 00181, Italy. FAU - Polenzani, Lorenzo AU - Polenzani L AD - Angelini RR&D (Research, Regulatory & Development), Angelini S.p.A., Rome, 00181, Italy. FAU - Assfalg, Michael AU - Assfalg M AD - Department of Biotechnology, University of Verona, Verona, 37129, Italy. FAU - Caltagirone, Carlo AU - Caltagirone C AD - European Center for Brain Research (CERC)/Santa Lucia Foundation IRCCS, Rome, 00143, Italy. FAU - Dainese, Enrico AU - Dainese E AUID- ORCID: 0000-0001-7163-9344 AD - Faculty of Veterinary Medicine, University of Teramo, Teramo, 64100, Italy. FAU - Maccarrone, Mauro AU - Maccarrone M AUID- ORCID: 0000-0002-3990-2963 AD - European Center for Brain Research (CERC)/Santa Lucia Foundation IRCCS, Rome, 00143, Italy. m.maccarrone@unicampus.it. AD - Department of Medicine, Campus Bio-Medico University of Rome, Rome, 00128, Italy. m.maccarrone@unicampus.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191022 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Chemokine CCL2) RN - 0 (FABP4 protein, human) RN - 0 (Fatty Acid-Binding Proteins) RN - 0 (Immunologic Factors) RN - 0 (Indazoles) RN - 0 (Interleukin-8) RN - 0 (Lipopolysaccharides) RN - 0 (PPAR gamma) RN - 0 (Propionates) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - JQ11LH711M (bindarit) SB - IM MH - Active Transport, Cell Nucleus/drug effects MH - Anti-Inflammatory Agents/chemistry/*pharmacology MH - Cell Line MH - Cell Nucleus/drug effects/metabolism MH - Chemokine CCL2/metabolism MH - Fatty Acid-Binding Proteins/chemistry/genetics/*metabolism MH - Humans MH - Immunologic Factors/pharmacology MH - Indazoles/chemistry/*pharmacology MH - Interleukin-8/metabolism MH - Lipopolysaccharides MH - Models, Biological MH - Monocytes/drug effects/*metabolism MH - PPAR gamma/metabolism MH - Propionates/chemistry/*pharmacology MH - Protein Binding/drug effects MH - Up-Regulation/drug effects MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC6805920 COIS- I.C., M.A.A. and L.P. were employed by Angelini at the time of manuscript preparation and submission. Angelini did not influence experimental design nor interpretation of results. C.C. was the Scientific Director of the Institute, and M.M. was the Director of the Research Unit that received funding from Angelini to explore molecular mechanisms of action of bindarit. The remaining authors declare that no competing - both financial and non-financial - interests exist. EDAT- 2019/10/24 06:00 MHDA- 2020/10/29 06:00 PMCR- 2019/10/22 CRDT- 2019/10/24 06:00 PHST- 2019/07/05 00:00 [received] PHST- 2019/10/07 00:00 [accepted] PHST- 2019/10/24 06:00 [entrez] PHST- 2019/10/24 06:00 [pubmed] PHST- 2020/10/29 06:00 [medline] PHST- 2019/10/22 00:00 [pmc-release] AID - 10.1038/s41598-019-51691-y [pii] AID - 51691 [pii] AID - 10.1038/s41598-019-51691-y [doi] PST - epublish SO - Sci Rep. 2019 Oct 22;9(1):15155. doi: 10.1038/s41598-019-51691-y.