title: Impact of the anti-inflammatory agent bindarit on the chemokinome: selective inhibition of the monocyte chemotactic proteins.
abstract: Bindarit is an indazolic derivative that is devoid of any immunosuppressive effects and has no effect on arachidonic acid metabolism. However, it has been proved to have anti-inflammatory activity in a number of experimental diseases, including pancreatitis, arthritis, and lupus nephritis. This therapeutic effect has been associated with its ability to interfere selectively with monocyte recruitment, although the underlying molecular mechanisms are unknown. Here we comprehensively examine the effect of bindarit on the chemokine system, and report that in activated monocytes and endothelial cells, it selectively inhibits the production of the monocyte chemotactic protein subfamily of CC inflammatory chemokines (MCP-1/CCL2, MCP-3/CCL7, MCP-2/CCL8). The capacity of bindarit to inhibit the production of a defined set of related CC chemokines by monocytes and endothelial cells likely underlies the anti-inflammatory activity of this agent in disease. The exploitation of the chemokine system as drug target in inflammatory disease has relied mainly on the development of receptor antagonists and blocking antibodies. Here we report on the use of inhibition of synthesis as a potentially viable and selective approach to modify the chemokine system.
authors.affiliation: Istituto Clinico Humanitas IRCCS, Rozzano, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mirolo
authors.forename: Marco
authors.initials: M
authors.lastname: Fabbri
authors.forename: Marina
authors.initials: M
authors.lastname: Sironi
authors.forename: Annunciata
authors.initials: A
authors.lastname: Vecchi
authors.forename: Angelo
authors.initials: A
authors.lastname: Guglielmotti
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mangano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biondi
authors.forename: Massimo
authors.initials: M
authors.lastname: Locati
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism; D054412:Chemokine CCL8 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D054412:Chemokine CCL8; D007191:Indazoles; D018945:Monocyte Chemoattractant Proteins; D011422:Propionates; C079489:bindarit