The Janus kinase (JAK) 2 -signal transducer and activator of transcription (STAT) signaling pathway is the major signaling pathway activated by the type I (IFN␣ and IFN␤) and type II (IFN␥) interferons, key immune regulatory cytokines (1, 2). IFN␥, a potent inflammatory cytokine and macrophage activator, predominantly activates STAT1 that mediates the inflammatory, pro-apoptotic, and anti-proliferative effects of this cytokine (3, 4). IFN␥ only weakly activates STAT3, which opposes the biological functions of STAT1 and mediates anti-inflammatory, anti-apoptotic, and proliferative effects (5-7). In contrast to IFN␥, the pleiotropic cytokine IL-6 activates both STAT1 and STAT3, and the anti-inflammatory cytokine IL-10 activates predominantly STAT3 (8, 9). STAT1 and STAT3 oppose each others activation by the IFN␥ and IL-6 receptors, and this mutual antagonism results in an integrated signal that can be fine tuned depending on cellular context (5, 8, 10). Mechanisms of negative cross-regulation by STAT1 and STAT3 include competition for common receptor docking sites and STAT3-dependent activation of SOCS3 expression (5, 7, 10 -16). SOCS3, in turn, regulates IL-6 signaling by binding to STAT docking sites in the IL-6 receptor, attenuating JAK activation, and suppressing downstream STAT activation (7,(11)(12)(13)(14)(15)(16).Type I IFNs are pleiotropic cytokines that have potent antiviral activity and promote the transition from innate to acquired immunity, but can also suppress inflammatory responses and diseases such as multiple sclerosis and inflammatory bowel disease (2, 17-20). The receptor for type I interferons consists of two subunits, IFNAR-1 and IFNAR-2, that are associated with the JAK tyrosine kinases Tyk2 and Jak1, respectively, which are in turn responsible for downstream activation of multiple STATs. IFN␣ can activate all of the known STATs, but in myeloid cells activates predominantly STAT1, STAT2, and STAT3 (17,20). Tyrosine-phosphorylated STAT1 and STAT2, together with IFN regulatory factor 9 (IRF-9), assemble into the heterotrimeric IFN-stimulated gene factor 3 (ISGF-3) complex that binds to the IFN-stimulated response element (ISRE) and initiates transcription that accounts for many of the antiviral and growth inhibitory properties of type I IFNs (17). In addition, IFN␣ stimulation leads to the formation of STAT1 homodimers that bind to ␥-activated sequence (GAS) promoter elements and activate canonical IFN␥-induced STAT1-dependent genes (7,21,22). Activation of these genes can explain some of the immunomodulatory effects of type I IFNs. We have recently reported that increased activation of STAT1 by IFN␣ in IFN␥-primedmacrophagesresultedinincreasedactivationofSTAT1-dependent inflammatory genes, such as the chemokines CXCL9 (Mig) and CXCL10 (inducible protein-10) (22). One important determinant of increased STAT1 activation by IFN␣ in primed macrophages was the increased level of STAT1 expression relative to expression of STAT2 and STAT3.IFN␣ strongly activates STAT3, but the functional consequence...

, IBM announced the start of a five-year effort to build a massively parallel computer, to be applied to the study of biomolecular phenomena such as protein folding. The project has two main goals: to advance our understanding of the mechanisms behind protein folding via large-scale simulation, and to explore novel ideas in massively parallel machine architecture and software. This project should enable biomolecular simulations that are orders of magnitude larger than current technology permits. Major areas of investigation include: how to most effectively utilize this novel platform to meet our scientific goals, how to make such massively parallel machines more usable, and how to achieve performance targets, with reasonable cost, through novel machine architectures. This paper provides an overview of the Blue Gene project at IBM Research. It includes some of the plans that have been made, the intended goals, and the anticipated challenges regarding the scientific work, the software application, and the hardware design.

A key function of interferons is priming multiple cell types for enhanced activation by cytokines and inflammatory factors, including tumor necrosis factor, bacterial lipopolysaccharide and interferons themselves. Here we show that interferon-alpha (IFN-alpha)-induced activation of the transcriptional activator STAT1 and inflammatory STAT1 target genes was enhanced in IFN-gamma-primed macrophages. Enhanced IFN-alpha signaling and proinflammatory function were dependent on the tyrosine kinase Syk and on adaptor proteins that activate Syk through immunoreceptor tyrosine activation motifs. Increased STAT1 expression contributed to enhanced IFN-alpha-induced STAT1 activation in primed macrophages. These results identify a mechanism by which crosstalk between cytokine and immune cell-specific immunoreceptor tyrosine activation motif-dependent signaling pathways regulates macrophage responses to IFN-alpha.

A G protein–coupled receptor (GPCR) is encoded within the genome of Kaposi's sarcoma– associated herpesvirus (KSHV)/human herpesvirus 8, a virus that may be involved in the pathogenesis of Kaposi's sarcoma and primary effusion lymphomas. KSHV-GPCR exhibits constitutive signaling activity that causes oncogenic transformation. We report that human interferon (IFN)-γ–inducible protein 10 (HuIP-10), a C-X-C chemokine, specifically inhibits signaling of KSHV-GPCR. In contrast, monokine induced by IFN-γ (HuMig), which like HuIP-10 is an agonist of C-X-C chemokine receptor 3, does not inhibit KSHV-GPCR signaling. Moreover, HuIP-10, but not HuMig, inhibits KSHV-GPCR–induced proliferation of NIH 3T3 cells. These results show that HuIP-10 is an inverse agonist that converts KSHV-GPCR from an active to an inactive state. Thus, a human chemokine inhibits constitutive signaling and cellular proliferation that is mediated by a receptor encoded by a human disease-associated herpesvirus.