Submitted March 31, 2006
Accepted April 24, 2006
Histone deacetylase inhibitors prevent exocytosis of
interleukin-1
-containing secretory lysosomes:
role of microtubules
Sonia Carta, Sara Tassi, Claudia Semino, Gianluca Fossati, Paolo Mascagni, Charles A Dinarello, and Anna Rubartelli*
Laboratory of Experimental Oncology E, National Cancer Research Institute, Genova, Italy
Center for Research, Italfarmaco, Cinisello Balsamo, Milano, Italy
Department of Medicine, University of Colorado at Denver & Health Sciences Center, Denver, CO, USA
* Corresponding author; email: anna.rubartelli{at}istge.it.
A number of agents reducing IL-1
activity are
being developed as novel immunomodulatory and anti-
inflammatory therapies. However, the elucidation of
their molecular mechanism of action is required in the
context of medical management of inflammatory diseases.
Inhibitors of histone deacetylases (HDAC) are promising
anticancer agents with pleiotropic activities. Of these,
suberoylanilide hydroxamic acid has been reported to
inhibit the production of several pro-inflammatory
cytokines. In the present study, we investigated the
effects of two HDAC inhibitors on IL-1 secretion:
suberoylanilide hydroxamic acid and a newly developed
hydroxamic acid-derived compound ITF2357. These HDAC
inhibitors do not affect the synthesis or intracellular
localization of IL-1 but both strongly reduce the
levels of extracellular IL-1 by preventing the
exocytosis of IL-1-containing secretory
lysosomes. At nanomolar concentrations, ITF2357 reduces
the secretion of IL-1 following ATP activation of
the P2X7 receptor. Whereas the inhibition of HDAC
results in hyperacetylation of tubulin, acetylation of
HSP90 was unaffected. The reduction in IL-1
secretion appears to be due to disruption of
microtubules impairing lysosome exocytosis. Together,
these observations indicate that a functional
microtubule network is required for IL-1
secretion and suggest that disruption of tubulin is the
mechanism by which inhibitors of HDAC reduce the
secretion of IL-1.
