Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (2629)	3/17/2006 10:55:16 AM
From: tuck	Respond to of 3044

Deleted, sorry

To: Icebrg who wrote (2629)	3/17/2006 10:55:33 AM
From: tuck	Respond to of 3044

[Bortezomib modulates TLR4-induced dendritic cell activation] >>Blood. 2006 Mar 14; [Epub ahead of print] The proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Nencioni A, Schwarzenberg K, Brauer KM, Schmidt SM, Ballestrero A, Grunebach F, Brossart P. Department of Internal Medicine, University of Genova, Genova, Italy. Evidence from the animal model suggests that proteasome inhibitors may have immunosuppressive properties, however their effects on the human immune system remain poorly investigated. Here, we show that bortezomib, a proteasome inhibitor with anticancer activity, impairs several immune properties of human monocyte-derived dendritic cells (DCs). Namely, exposure of DCs to bortezomib reduces their phagocytic capacity, as shown by FITC-labelled dextran internalization and mannose-receptor CD206 downregulation. DCs treated with bortezomib show skewed phenotypic maturation in response to stimuli of bacterial (lipopolysaccharide (LPS)) and endogenous source (including TNF-alpha and CD40L), as well as reduced cytokine production and immunostimulatory capacity. LPS-induced CCL-2/MCP-1 and CCL5/RANTES secretion by DCs were prevented by DC treatment with bortezomib. Finally, CCR7 upregulation in DC exposed to LPS as well as migration toward CCL19/MIP-3beta were strongly impaired. As a suitable mechanism for these effects, bortezomib was found to downregulate MyD88, an essential adaptor for TLR signalling, and to relieve LPS-induced activation of NF-kappaB, IRF-3, IRF-8 and of the MAP kinase pathway. In summary, inhibition of DC function may represent a novel mechanism by which proteasome inhibitors exert immunomodulatory effects. These compounds could prove useful for tuning TLR signalling and for the treatment of inflammatory and immune-mediated disorders.<< Cheers, Tuck