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Biotech / Medical : Tularik Inc. (TLRK) -- Ignore unavailable to you. Want to Upgrade?

To: Czechsinthemail who wrote (312)	9/17/2002 11:28:32 AM
From: scaram(o)uche	Read Replies (1) \| Respond to of 598

J Biol Chem 1999 Jul 30;274(31):21569-74 HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8. Agonist and antagonist profiles of viral chemokines. Dairaghi DJ, Fan RA, McMaster BE, Hanley MR, Schall TJ. Divisions of Discovery Biology and Molecular Pharmacology, ChemoCentryx, San Carlos, California 94070, USA. Uncertainty regarding viral chemokine function is mirrored by an incomplete knowledge of host chemokine receptor usage by the virally encoded proteins. One such molecule is vMIP-I, a C-C type chemokine of undefined function and binding specificity, encoded by the Kaposi's sarcoma herpesvirus HHV-8. We report here that vMIP-I binds to and induces cytosolic [Ca(2+)] signals in human T cells selectively through CCR8, a CC chemokine receptor associated with Th2 lymphocytes. Furthermore, using a panel of 65 different human, viral, and rodent chemokines, we have established a comprehensive ligand binding "fingerprint" for CCR8. The receptor exhibits marked "high" affinity (K(d) < 15 nM) only for four chemokines, three of them of viral origin: vMIP-I, vMIP-II, vMCC-I, and human I-309. A previously unreported second class of lower affinity ligands includes MCP-3 and possibly two other viral chemokines. vMIP-I and I-309 appear to act as CCR8 agonists: binding to and inducing cytosolic [Ca(2+)] elevation through the receptor. By contrast, vMIP-II and vMCC-I act as potent antagonists: binding without inducing signaling, and blocking the effects of I-309 and vMIP-I. These results suggest a ligand hierarchy for CCR8, identifying vMIP-I as a selective viral chemokine agonist. CCR8 may thus engage a specific subset of chemokines with the potential to regulate each other during viral infection and immune regulation. J Virol 2002 Feb;76(3):1285-92 Erratum in: J Virol 2002 Apr;76(7):3585 Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. Spencer JV, Lockridge KM, Barry PA, Lin G, Tsang M, Penfold ME, Schall TJ. ChemoCentryx, San Carlos, California 94070, USA. Cytomegalovirus (CMV) has highly evolved mechanisms for avoiding detection by the host immune system. Recently, in the genomes of human and primate CMV, a novel gene comprising segments of noncontiguous open reading frames was identified and found to have limited predicted homology to endogenous cellular interleukin-10 (IL-10). Here we investigate the biological activities of the CMV IL-10-like gene product and show it to possess potent immunosuppressive properties. Both purified bacterium-derived recombinant CMV IL-10 and CMV IL-10 expressed in supernatants of human cells were found to inhibit proliferation of mitogen-stimulated peripheral blood mononuclear cells (PBMCs), with specific activity comparable to that of recombinant human IL-10. In addition, CMV IL-10 expressed from human cells inhibited cytokine synthesis, as treatment of stimulated PBMCs and monocytes with CMV IL-10 led to a marked decrease in production of proinflammatory cytokines. Finally, CMV IL-10 was observed to decrease cell surface expression of both major histocompatibility complex (MHC) class I and class II molecules, while conversely increasing expression of the nonclassical MHC allele HLA-G. These results demonstrate for the first time that CMV has a biologically active IL-10 homolog that may contribute to immune evasion during virus infection.