Showing papers by "Gregory G. Freund published in 2001"
TL;DR: The multiple functions of IL-10 in the brain will create new and intriguing vistas that will promote a better understanding of neurodegenerative diseases and could lead to development of innovative approaches for the use of antiinflammatory cytokines in major debilitating diseases of the CNS.
Abstract: Interleukin (IL)-10 is synthesized in the central nervous system (CNS) and acts to limit clinical symptoms of stroke, multiple sclerosis, Alzheimer's disease, meningitis, and the behavioral changes that occur during bacterial infections. Expression of IL-10 is elevated during the course of most major diseases in the CNS and promotes survival of neurons and all glial cells in the brain by blocking the effects of proapoptotic cytokines and by promoting expression of cell survival signals. Stimulation of IL-10 receptors regulates numerous life- or death-signaling pathways--including Jak1/Stat3, PI 3-kinase, MAPK, SOCS, and NF-kappaB--ultimately promoting cell survival by inhibiting both ligand- and mitochondrial-induced apoptotic pathways. IL-10 also limits inflammation in the brain; it does so by three major pathways: (1) reducing synthesis of proinflammatory cytokines, (2) suppressing cytokine receptor expression, and (3) inhibiting receptor activation. Finally, IL-10 induces anergy in brain-infiltrating T cells by inhibiting cell signaling through the costimulatory CD28-CD80/86 pathway. The multiple functions of IL-10 in the brain will create new and intriguing vistas that will promote a better understanding of neurodegenerative diseases. These discoveries could lead to development of innovative approaches for the use of antiinflammatory cytokines in major debilitating diseases of the CNS.
374 citations
TL;DR: It is established that activation of the IL-10R promotes survival of progenitor myeloid cells by stimulating the insulin receptor substrate-2/PI 3-kinase/Akt pathway, which increases the anti-apoptotic activity of ERK1/2.
Abstract: IL-10 is well known to be a potent inhibitor of the synthesis of proinflammatory cytokines, but noninflammatory hemopoietic cells also express IL-10Rs. Here we show that IL-10 directly affects progenitor myeloid cells by protecting them from death following the removal of growth factors. Murine factor-dependent cell progenitors cultured in the absence of growth factors were 43 ± 1% apoptotic after 12 h. Addition of IL-10 at a concentration as low as 100 pg/ml significantly reduced the apoptotic population to 32 ± 3%. At 10 ng/ml, IL-10 caused a 4-fold reduction in the apoptotic population (11 ± 1%). The anti-apoptotic activity of IL-10 was significantly inhibited with a neutralizing IL-10R Ab. Factor-dependent cell progenitor promyeloid cells expressed functional IL-10Rs, as assessed by precipitation of a 110-kDa protein with an Ab to the IL-10R and by the ability of IL-10 to activate Jak1 and Tyk2 and to phosphorylate tyrosine 705 on Stat-3. IL-10 increased tyrosyl phosphorylation of insulin receptor substrate-2 and stimulated the enzymatic activity of both phosphatidylinositol 3′-kinase and Akt. The anti-apoptotic activity of IL-10 was blocked by inhibition of phosphatidylinositol 3′-kinase. Wortmannin and LY294002 also totally inhibited activation of extracellular signal-related kinase (ERK)1/2 by IL-10. Direct inhibition of ERK1/2 with the mitogen-activated protein kinase/ERK kinase inhibitor PD98059 partially, but significantly, impaired the anti-apoptotic activity of IL-10. These data establish that activation of the IL-10R promotes survival of progenitor myeloid cells. This survival-promoting activity is totally due to IL-10 stimulating the insulin receptor substrate-2/PI 3-kinase/Akt pathway, which increases the anti-apoptotic activity of ERK1/2.
75 citations
TL;DR: CD45 negatively regulates monocyte differentiation by inhibiting phorbol 12-myristate 13-acetate (PMA)-dependent activation of protein kinase C (PKC) δ by impeding PMA-dependent PKCδ tyrosine phosphorylation, suggesting that CD45 is a critical regulator of monocytic cell development.
47 citations
TL;DR: It is reported that FKBP12-rapamycin-associated protein (FRAP) is a physiologic IRS-1 kinase that blocks IFN alpha signaling by serine phosphorylating IRS- 1 and suggests that FRAP may modulate IRS-dependent cytokine signaling.
36 citations
TL;DR: Evidence is offered that the combined effects of IGF-I and TNFα on neuronal survival can be vastly different when both receptors are stimulated simultaneously, as is likely to occur in vivo.
35 citations