Arterial hypertension is the most common cardiovascular disease

in response to RANKL. Thus, CD11b+F4/80+Ly6C+Gr1- M1 macrophages are authentic OCPs. However, both Ly6C+Gr1- and Ly6C-Gr1- cells primed by TNF have significantly enhanced OC forming potential, and both cell populations have increased expression of the M1 surface marker, CD11c, and express the M1 effector molecules, iNOS, TGF1 and IL-1, suggesting that these cells have been switched to a M1 phenotype. In addition, TNF-primed Ly6C+/-Gr1+CD11b+F4/80+ cells form OCs in response to RANKL, although the numbers are small. This population could be similar to our previously identified CD11b+Gr1+/- OCPs in TNF-Tg mice. With all of these features, it is not surprising that TNF did not inhibit RANKL-induced OC formation from TNF-primed OCPs. Robust induction of OC formation by TNF from RANKL-primed OCPs probably reflects the fact that these cells are already well along the OC differentiation process since NFATc1 expression was significantly increased within 24 hours of RANKL treatment. In general, the transcription factor, PU.1, controls the global macrophage-specific enhancer repertoire, irrespective of polarization. In response to M1-inducing stimuli, transcription factors, signal transducer and activator of transcription 1 and interferon-regulatory factor 5 are activated to polarize M1 macrophages, while factors that activate STAT6, IRF4 and peroxisome proliferator activated receptor- control the polarization of M2 macrophages. NF-B p50 and p65 have been identified as regulators of macrophage polarization and cytokine production. p50 is considered as a key component in the orchestration of M2-driven inflammatory reactions. It inhibits M1-polarization and IFN- production, and p50-deficient mice show exacerbated M1-driven inflammation and defective capacity to mount allergy-driven M2-polarized inflammatory reactions. Similarly, transfection of p50 siRNA into M2-like macrophages resulted in a significant decrease in expression of the M2 marker, IL-10, and increased production of the M1 markers, IL-12, TNF- and IL-6. Hyperacetylated p65 and increased NF-B binding activity in bone marrow cells with targeted deletion of mammalian sirtuin member 1 in myeloid PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19729663 cells resulted in increased M1 polarization, migration, and pro-inflammatory cytokine production, suggesting that p65 also plays an important role in M1 activation. Here, we report a novel mechanism by which TNF induction of M1 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19728767 macrophages is through NF-B RelB, based on our findings that TNF significantly increased RelB protein levels associated with switching of M-CSF-induced SKI II price Ly6C-Gr1-CD11c- M2 to Ly6C+Gr1- and Ly6C-Gr1-CD11c+ M1 F4/80+CD11b+ macrophages, while TNF induction of Ly6C+Gr1- and Ly6C-Gr1-CD11c+ M1 macrophages does not occur in RelB-/- bone marrow cells. The role of RelB in OC differentiation is also poorly understood. OC numbers in the bones of RelB-/- mice are normal in vivo, while RANKL-induced OC formation from RelB-/- myeloid progenitors is impaired in vitro, and cancer-induced osteolysis is reduced in RelB-/- mice in vivo. These findings suggest that RelB is not required for basal OC formation, but appears to play a positive role in the enhanced osteoclastogenesis in pathologic conditions. Contrary to the reported positive role for RelB in OC differentiation, we found that RelB itself functions as a transcriptional repressor of NFATc1 to inhibit terminal OC differentiation based on our findings that: 1) TNF inhibits RANKL-induced OC formation and NFATc1 mRNA 16 / 20 TNF Induced O