NDLI: Intensity of macrolide anti-inflammatory activity in J774A.1 cells positively correlates with cellular accumulation and phospholipidosis.

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Intensity of macrolide anti-inflammatory activity in J774A.1 cells positively correlates with cellular accumulation and phospholipidosis.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Munic, Vesna Banjanac, Mihailo Kostrun, Sanja Nujic, Krunoslav Bosnar, Martina Marjanovic, Nikola Ralic, Jovica Matijasic, Mario Hlevnjak, Mario Erakovic Haber, Vesna
Description	Country affiliation: Croatia Author Affiliation: Munic V ( GlaxoSmithKline Research Center Zagreb Ltd., Prilaz baruna Filipovica 29, HR-10000 Zagreb, Croatia. vesna.munic@glpg.com)
Abstract	Some macrolide antibiotics were reported to inhibit interleukin-6 (IL6) and prostaglandin-E2 (PGE(2)) production by bacterial lipopolysaccharide (LPS) stimulated J774A.1 cells. Macrolides are also known to accumulate in cells and some were proven inducers of phospholipidosis. In the present study, with a set of 18 mainly 14- and 15-membered macrolides, we have investigated whether these macrolide induced phenomena in J774A.1 cells are connected. In LPS-stimulated J774A.1 cells, the extent of inhibition of proinflammatory markers (IL6 and PGE(2)) by macrolides significantly correlated with their extent of accumulation in cells, as well as with the induction of phospholipidosis, and cytotoxic effects in prolonged culture (with correlation coefficients (R) ranging from 0.78 to 0.93). The effects observed were related to macrolide binding to phospholipids (CHI IAM), number of positively charged centres, and were inversely proportional to the number of hydrogen bond donors. Similar interdependence of effects was obtained with chloroquine and amiodarone, whereas for dexamethasone and indomethacin these effects were not linked. The observed macrolide induced phenomena in J774A.1 cells were reversible and elimination of the macrolides from the culture media prevented phospholipidosis and the development of cytotoxicity in long-term cultures. Based on comparison with known clinical data, we conclude that LPS-stimulated J774A.1 cells in presented experimental setup are not a representative cellular model for the evaluation of macrolide anti-inflammatory potential in clinical trials. Nevertheless, our study shows that, at least in in vitro models, binding to biological membranes may be the crucial factor of macrolide mechanism of action.
File Format	HTM / HTML
ISSN	10436618
Issue Number	3
Volume Number	64
e-ISSN	10961186
Journal	Pharmacological Research
Language	English
Publisher	Elsevier
Publisher Date	2011-09-01
Publisher Place	Netherlands
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Pharmacology Anti-bacterial Agents Immunology Anti-inflammatory Agents Macrolides Phospholipids Metabolism Animals Pharmacokinetics Pharmacology Binding Sites Cell Line Cell Membrane Permeability Cell Survival Drug Effects Dinoprostone Interleukin-6 Lipopolysaccharides Macrophages Mice Journal Article Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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Intensity of macrolide anti-inflammatory activity in J774A.1 cells positively correlates with cellular accumulation and phospholipidosis.

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Intensity of macrolide anti-inflammatory activity in J774A.1 cells positively correlates with cellular accumulation and phospholipidosis.