Cell adaptation to hypoxia (Hyp) requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via angiogenesis) and metabolic adaptation (via glycolysis). Here, we describe that oxygen availability is a determinant parameter in the setting of chemotactic responsiveness to stromal-derived factor 1 (CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor, CXC receptor 4 (CXCR4), in different cell types (monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells), which is paralleled by increased chemotactic responsiveness to its specific ligand. CXCR4 induction by Hyp is dependent on both activation of the Hyp-inducible factor 1 α and transcript stabilization. In a relay multistep navigation process, the Hyp–Hyp-inducible factor 1 α–CXCR4 pathway may regulate trafficking in and out of hypoxic tissue microenvironments.

We found that inflammatory stimuli induce p38 mitogen-activated protein kinase-dependent phosphorylation and phosphoacetylation of histone H3; this selectively occurred on the promoters of a subset of stimulus-induced cytokine and chemokine genes. p38 activity was required to enhance the accessibility of the cryptic NF-kappa B binding sites contained in H3 phosphorylated promoters, which indicated that p38-dependent H3 phosphorylation may mark promoters for increased NF-kappa B recruitment. These results show that p38 plays an additional role in the induction of the inflammatory and immune response: the regulation of NF-kappa B recruitment to selected chromatin targets.

The human homologue of Drosophila Toll (hToll) is a recently cloned receptor of the interleukin 1 receptor (IL-1R) superfamily, and has been implicated in the activation of adaptive immunity. Signaling by hToll is shown to occur through sequential recruitment of the adapter molecule MyD88 and the IL-1R–associated kinase. Tumor necrosis factor receptor–activated factor 6 (TRAF6) and the nuclear factor κB (NF-κB)–inducing kinase (NIK) are both involved in subsequent steps of NF-κB activation. Conversely, a dominant negative version of TRAF6 failed to block hToll-induced activation of stress-activated protein kinase/c-Jun NH2-terminal kinases, thus suggesting an early divergence of the two pathways.

We identified a viral IL-10 homolog encoded by an ORF (UL111a) within the human cytomegalovirus (CMV) genome, which we designated cmvIL-10. cmvIL-10 can bind to the human IL-10 receptor and can compete with human IL-10 for binding sites, despite the fact that these two proteins are only 27% identical. cmvIL-10 requires both subunits of the IL-10 receptor complex to induce signal transduction events and biological activities. The structure of the cmvIL-10 gene is unique by itself. The gene retained two of four introns of the IL-10 gene, but the length of the introns was reduced. We demonstrated that cmvIL-10 is expressed in CMVinfected cells. Thus, expression of cmvIL-10 extends the range of counter measures developed by CMV to circumvent detection and destruction by the host immune system. I L-10 is a pleiotropic immunomodulatory cytokine produced by CD4 ϩ and CD8 ϩ T cells, monocytes͞macrophages, keratinocytes, and activated B cells (1). In addition, its expression is elevated in patients with a variety of peripheral blood or bone marrow-derived leukemias, certain B cell and T cell lymphomas and nasal natural killer cell lymphomas and other hematopoietic and solid tumors (1-5). Two mechanisms of IL-10 action can be used by tumors. IL-10 appears to act as an autocrine growth factor for B cell lymphomas. In addition, IL-10 selectively inhibits certain aspects of the cellular immune response. It blocks proinflammatory cytokine synthesis and suppresses the ability of macrophages to serve as antigen-presenting or costimulatory cells (6-8). Thus, IL-10 is a powerful anti-inflammatory agent and a potent immunosuppressor.Many viruses exploit the strategy of using homologs of cellular cytokines or cytokine receptors to shield virus-infected cells from immune defenses and enhance virus survival in the host. The presence of virus-encoded homologs of cellular proteins may be an indicator of the importance of these cellular components in immune mechanisms for combating this virus in vivo. A number of herpes viruses harbor homologs of IL-10. Epstein-Barr virus (EBV)-encoded IL-10 (ebvIL-10), the first viral homolog of IL-10 identified (9, 10), shares many but not all of the biological activities of cellular IL-10 and may play an important role in the host-virus interaction (1,11,12). In addition to EBV, another virus, the Orf poxvirus (OV), which can infect humans, has its own IL-10 homolog, ovIL-10 (13). Whether it is active on human cells remains to be shown. The exact in vivo roles of viral IL-10 homologs in the viral life cycle, in immune evasion, and͞or in helping virus-infected cells to survive immune surveillance remain to be defined.Human cytomegalovirus (CMV) is a widespread herpes virus that is able to persist for decades in its host. CMV is the major cause of a variety of life-threatening diseases in immunocompromised individuals, including transplant and AIDS patients, and is a leading cause of congenital birth defects (14). CMV is also associated with the development of atherosclerosis, restenosis after coronary...

Proinflammatory stimuli induce the rapid and transient translocation of nuclear factor (NF)-κB to the nucleus, where it activates transcription from several genes, including those encoding inflammatory cytokines and chemokines, adhesion molecules, and cytoprotective proteins. Using chromatin immunoprecipitation, we show that after an acute stimulation two distinct waves of NF-κB recruitment to target promoters occur: a fast recruitment to constitutively and immediately accessible (CIA) promoters and a late recruitment to promoters requiring stimulus-dependent modifications in chromatin structure to make NF-κB sites accessible (promoters with regulated and late accessibility [RLA]). Our results suggest that a mechanism of specificity in NF-κB–dependent transcriptional responses relies on the ability of individual stimuli to make RLA promoters accessible to NF-κB before its rapid extrusion from the nucleus.