Macrophages, Inflammation, and Tumor Suppressors: ARF, a New Player in the Game

Figure 2

Alternative activation in ARF-deficient macrophages. In WT macrophages, a balance between M1 and M2 phenotype is established, depending on stimuli. Inflammatory stimuli induce NF-κB signaling pathways through the phosphorylation and subsequent ubiquitin-dependent degradation of IκBα by the 26S proteasome. Then, NF-κB translocates to the nucleus inducing target gene expression. ARF present in the nucleus displays physical and functional interaction with E2F1 resulting in destabilization of E2F1 protein and activation of NF-κB. However, ARF-deficient macrophages establish an immunosuppressive and tolerant microenvironment via impairment of M1 signals. When NF-κB translocates to the nucleus, excessive E2F1 inhibits NF-κB by binding to its subunit p65 in competition with the heterodimeric partner p50. Moreover, excessive E2F1 may inhibit transcriptional expression of TLRs. This leads to secretion of M2 chemokines Ccl17 and Ccl22, release of the anti-inflammatory cytokine IL-10, and stimulation of angiogenesis through expression of VEGF and MMP-9.