IL-1 signaling in the tumor microenvironment. IL-1 is a critical molecule in inflammation-associated carcinogenesis produced directly by tumor cells or cells of the tumor microenvironment. IL-1 signal transduction is initiated by binding of either form of IL-1 to IL-1 receptor type I (IL-1RI), which undergoes a conformational change allowing the IL-1 receptor accessory protein (IL-1RAcP) to recognize the ligated IL-1RI. IL-1RAcP does not recognize IL-1 but represents an essential component in the IL-1 signaling pathway (Wesche et al., 1997b; Radons et al., 2002). The naturally occurring IL-1 receptor antagonist (IL-1Ra) also binds to IL-1RI without leading to its activation. Ligand-mediated heterodimerization of the receptor complex leads to recruitment of dimeric myeloid differentiation protein 88 (MyD88) via its TIR domain (Muzio et al., 1997; Wesche et al., 1997a; Radons et al., 2003) followed by complex formation between IRAK-4, MyD88, and IL-1RAcP and subsequent phosphorylation of IRAK-4 (Cahill and Rogers, 2008). After recruitment of IRAK-1/Tollip to the complex, IRAK-1 is initially phosphorylated by IRAK-4 (Born et al., 1998; Dunne and O’Neill, 2003). Subsequently, IRAK-1 (and possibly IRAK-2) becomes hyperphosphorylated and dissociates into the cytoplasm where it binds TNF receptor-associated factor 6 (TRAF-6; Cao et al., 1996). IRAK-1 interacts with membrane-bound TAK-binding protein 2 (TAB-2) as well as TAK-1/TAB-1 complex (Dower and Qwarnstrom, 2003) followed by translocation of TAB-2 from the plasma membrane to the signalosome and subsequent partial activation of TAK-1 by TAB-2. IRAK-1, presumably as dimer or oligomer, enables dimerization of TRAF-6 resulting in its ubiquitination and activation. In close proximity to TAB-2, TAK-1 is partially activated followed by complete activation through polyubiquitinated TRAF-6 (Kishimoto et al., 2000; Martin and Wesche, 2002) enabling activation of numerous signaling cascades. Polyubiquitination of TRAF-6 obviously occurs through IRAK-2 (Keating et al., 2007). On the one hand, TAK-1 activates certain members of the MAP kinase family leading to activation of AP-1 and ATF (Ninomiya-Tsuji et al., 1999; O’Neill, 2000; Hefler et al., 2005; Blanco et al., 2008) the latter augmenting NF-κB-mediated transcription via transactivation (Jefferies and O’Neill, 2000; Cahill and Rogers, 2008). On the other hand, TAK-1 phosphorylates and activates IKK resulting in phosphorylation and inactivation of IκBα (Wang et al., 2001). Afterward, IκBα dissociates from the complex with NF-κB and undergoes proteasomal degradation. After phosphorylation, NF-κB translocates to the nucleus and activates NF-κB-dependent gene transcription (Chen and Greene, 2004). Inhibitors of NF-κB activation are indicated that suppress the inflammatory network in cancer development. IL-1 signaling also involves recruitment of PI3-kinase (PI3K) to the IL-1 receptor complex via the p85 regulatory subunit of PI3K (Reddy et al., 1997) and subsequent activation of AKT/PKB leading to IKK-dependent activation of NF-κB and AP-1 (Cahill and Rogers, 2008). Receptor ligation can also activate numerous G proteins resulting in activation of AP-1 and ATF mediated by several MAP kinases and an IκBα-independent transactivation of NF-κB (Singh et al., 1999; Jefferies and O’Neill, 2000). IL-1 signaling finally regulates gene expression of a great variety of tumorigenic factors including pro-angiogenic factors (IL-8, VEGF), growth factors (IL-6, GM-CSF), anti-apoptotic factors (Bcl-XL, c-FLIP), invasion-promoting factors (MMP-2, MMP-7, MMP-9, uPA), inflammatory enzymes (PGHS-2, LOX), prostaglandins, iNOS, chemokines (CCL2, CCL20, IL-8), and pro-inflammatory cytokines (IL-1, IL-6, IL-23, TNF, TGF-β, EGF, RANKL).