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Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that patrol tissues to sense danger signals and activate specific immune responses. In addition, they also play a role in inflammation and tissue repair. Here, we show that oxygen availability is necessary to promote full monocyte-derived DC differentiation and maturation. Low oxygen tension (hypoxia) inhibits expression of several differentiation and maturation markers (CD1a, CD40, CD80, CD83, CD86, and MHC class II molecules) in response to lipopolysaccharide (LPS), as well as their stimulatory capacity for T-cell functions. These events are paralleled by impaired up-regulation of the chemokine receptor CCR7, an otherwise necessary event for the homing of mature DCs to lymph nodes. In contrast, hypoxia strongly upregulates production of proinflammatory cytokines, particularly TNF␣ and IL-1␤, as well as the inflammatory chemokine receptor CCR5. Subcutaneous injection of hypoxic DCs into the footpads of mice results in defective DC homing to draining lymph nodes, but enhanced leukocyte recruitment at the site of injection. Thus, hypoxia uncouples the promotion of inflammatory and tissue repair from sentinel functions in DCs, which we suggest is a safeguard mechanism against immune reactivity to damaged tissues. (Blood. 2008;112:3723-3734) IntroductionLow oxygen tension (hypoxia) has been described at virtually every site of extensive inflammation, including necrotic foci and cutaneous sites of infection and wounding. 1 Sites of inflammation are also characterized by extensive infiltration of inflammatory leukocytes, which need to move against oxygen gradients. As a consequence, immune effector cells in hypoxic sites, including dendritic cells (DCs), have an acute need to respond to these demanding conditions to maintain their viability and activity. DCs are powerful antigen-presenting cells (APCs) specialized for the activation of resting T cells and the initiation and regulation of many types of immune response. [2][3][4][5] Because of this, we have investigated the functional changes that accompanying the metabolic adaptation of DCs to hypoxia, as these events are likely to affect the development of both inflammatory and immune functions.The capacity of DCs to activate and regulate T-cell responses is acquired during a complex differentiation and maturation program. [2][3][4][5] DCs originate from bone marrow and, at an "immature" stage, they patrol peripheral tissues for the presence of pathogenassociated antigens. In order to perform this function, DCs express a rich repertoire of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), which permit DCs to recognize distinct pathogen-associated molecules. 6,7 The engagement of TLRs initiates a cascade of signaling events in DCs that leads, in the process of "maturation," to the secretion of inflammatory and immunomodulatory factors, which mediate protective immunity. 6,7 For instance, stimulation of DC by lipopolysaccharide (LPS), through the participation of TLR4, lead...

The transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8-PU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRF-AP-1 sites, which were not premarked by PU.1 and did not contribute to the basal IRF8 cistrome. While constitutively expressed IRF8-dependent genes contained only sites mediating basal IRF8/PU.1 recruitment, inducible IRF8-dependent genes contained variable combinations of constitutive and inducible sites. Overall, these data show at the genome scale how the same TF can be linked to constitutive and inducible gene regulation via distinct combinations of alternative DNA-binding sites.

Tumor-associated macrophages (TAM) have been linked with the progression of cancer by favoring tumor angiogenesis, growth, and metastasis. The precise mechanisms that maintain the protumor phenotype of TAM are poorly understood, but recent research has highlighted a number of signaling pathways that are important in TAM phenotype and function. Nuclear factor-κB (NF-κB) is considered the master regulator of inflammatory and immune responses. Recently several genetic studies have indicated NF-κB is an important pathway in TAM for the integration of signals from the tumor microenvironment that promote carcinogenesis. This review will focus on the role of NF-κB in TAM and the potential of targeting this pathway as a novel therapeutic strategy against cancer. Clin Cancer Res; 16(3); 784-9. ©2010 AACR.