Fri, 08 Aug 2008 20:04:21 BST CiteULike: AlfonsoVicenteSuarezs akt-il-10 http://www.citeulike.org/user/AlfonsoVicenteSuarez/tag/akt-il-10 CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/AlfonsoVicenteSuarez/article/1368794 <i>Immunol Res, Vol. 34, No. 1. (2006), pp. 33-48.</i><br /><br />Toll-like receptors (TLRs) play a crucial role in the innate immune system as a first line of defense against pathogens. TLR activation in phagocytes produces pro-inflammatory cytokines and chemokines that contribute directly to elimination of infectious agents and activation of adaptive immune responses. However, a sustained inflammatory response can result in tissue damage and generalized sepsis. This review summarizes the complex and sometimes conflicting links of TLR signaling with two important regulators of immune cells functions: phosphoinositide 3-kinases (PI3Ks) and small GTPases of the Rho family. A unified model of hierarchical organization of these signaling participants is still premature, given that the tools for delineating how control of TLRmediated pathways is achieved are just emerging. Critical progress in our understanding of spatial-temporal propagation of TLR signaling will certainly be provided in the near future by pharmacological targeting of PI3Ks using recently characterized, second-generation PI3K inhibitors in combination with gene-targeting strategies for PI3K subunits and Rho GTPases targeted to the murine myeloid compartment. New players in TLR-mediated innate immunity: PI3K and small Rho GTPases. M Ruse UG Knaus Immunol Res, Vol. 34, No. 1. (2006), pp. 33-48. 2007-06-06T17:57:49-00:00 2006 Immunol Res 0257-277X 34 1 33 48 akt-il-10 http://www.citeulike.org/user/AlfonsoVicenteSuarez/article/1368754 <i>J Immunol, Vol. 173, No. 1. (1 July 2004), pp. 360-366.</i><br /><br />LPS stimulates monocytes/macrophages through TLR4, resulting in the activation of a series of signaling events that potentiate the production of inflammatory mediators. Recent reports indicated that the inflammatory response to LPS is diminished by PI3K, through the activation of the serine/threonine kinase Akt. SHIP is an inositol phosphatase that can reverse the activation events initiated by PI3K, including the activation of Akt. However, it is not known whether SHIP is involved in TLR4 signaling. In this study, we demonstrate that LPS stimulation of Raw 264.7 mouse macrophage cells induces the association of SHIP with lipid rafts, along with IL-1R-associated kinase. In addition, SHIP is tyrosine phosphorylated upon LPS stimulation. Transient transfection experiments analyzing the function of SHIP indicated that overexpression of a wild-type SHIP, but not the SHIP Src homology 2 domain-lacking catalytic activity, up-regulates NF-kappaB-dependent gene transcription in response to LPS stimulation. These results suggest that SHIP positively regulates LPS-induced activation of Raw 264.7 cells. To test the validity of these observations in primary macrophages, LPS-induced events were compared in bone marrow macrophages derived from SHIP(+/+) and SHIP(-/-) mice. Results indicated that LPS-induced MAPK phosphorylation is enhanced in SHIP(+/+) cells, whereas Akt phosphorylation is enhanced in SHIP(-/-) cells compared with SHIP(+/+) cells. Finally, LPS-induced TNF-alpha and IL-6 production was significantly lower in SHIP(-/-) bone marrow-derived macrophages. These results are the first to demonstrate a role for SHIP in TLR4 signaling, and propose that SHIP is a positive regulator of LPS-induced inflammation. Lipopolysaccharide-induced macrophage inflammatory response is regulated by SHIP. H Fang RA Pengal X Cao LP Ganesan MD Wewers CB Marsh S Tridandapani J Immunol, Vol. 173, No. 1. (1 July 2004), pp. 360-366. 2007-06-06T17:37:42-00:00 2004 J Immunol 0022-1767 173 1 360 366 akt-il-10