survival have been well documented. By contrast, STAT1 inhibits tumor cell growth (56). JAK-mediated STAT tyrosine phosphory- lation allows dimerization, nuclear translocation, and activation of specific target genes (57). Most IL-6 target genes are involved in cell cycle progression and suppression of apoptosis, which underscores the importance of IL-6 in tumorigenesis (58).
IL-6 is suggested to have a pivotal role in the pathogenesis of Kaposi sarcoma (59) and MM (60). Recent studies also sug- gest an association between circulating IL-6 and elevated risk of developing Hodgkin lymphoma (61). Furthermore, a promoter polymorphism study suggests that IL6 is a predisposing genetic factor that contributes to breast cancer prognosis, with a G/C polymorphism within the promoter region of the IL6 gene that is associated with high levels of IL-6 production correlating with a worse prognosis (62). Clear evidence that IL-6 governs the growth of MM, a malignant disorder of plasma cells, has come from studies using Il6–/– mice, which were found to be resistant to plasmacytoma induction (63). In MM, IL-6 is produced by stromal cells in the bone marrow, and its synthesis by these cells can be further enhanced by their interaction with malignant plasma cells (64). Furthermore, in response to infection-activat- ed TLR signaling, MM cells also produce IL-6, which promotes their growth in an autocrine manner (41). New IL-6 antagonists are being evaluated for treatment of MM (65).
gesting an important role for IL-17 in localizing and amplifying inflammation (74–76). Furthermore, TNF-α and IL-6, which are both produced by Th17 cells, not only support Th17 cell develop- ment but also synergize with IL-17 to enhance the production of proinflammatory mediators (76).
Several studies have begun to address the role of IL-17 in chronic inflammation and cancer (72). IL-17–overexpressing human cervical cancer cells and non–small cell lung carcinoma (NSCLC) cells show substantially greater ability to form tumors in immunocompromised mice compared with control cells not overexpressing IL-17 (77, 78). Similarly, IL-17 overexpression in fibrosarcoma cell lines enhances their tumorigenic growth in C57BL/6 mice (79). This tumor-promoting effect has mainly been attributed to the proangiogenic activity of IL-17 (77, 78). In primary NSCLC samples, IL-17 expression has frequently been detected in tumor-infiltrating inflammatory cells and was associated with increased tumor vascularity (78). However, enhanced cervical cancer growth elicited by IL-17 was associated with increased expression of IL-6 and macrophage recruitment to the tumor sites (77). Therefore, IL-17 might also function through IL-6 to promote tumor development. A potential role for IL-17 in promoting human cervical cancer is suggested by its frequent expression in patients whose tumors show CD4+ T cell infiltration (77).
IBD is associated with high concentrations of IL-6 (32). Anti- body-mediated inhibition of IL-6 signaling retarded development of chemical-induced colitis-associated colon cancer (CAC) (66). CAC development can also be retarded by deleting the gene encod- ing IKKβ in myeloid cells, a process that is known to interfere with IL-6 production during early carcinogenesis (67). Importantly, deletion of the gene encoding IKKβ in myeloid cells and inhibition of IL-6 signaling decrease tumor size (66, 67), suggesting that IL-6 is mostly responsible for stimulation of tumor growth in these models of cancer (Figure 3).
In addition to classic IL-6 signaling, secretion of soluble IL-6 receptor (sIL-6R) can trigger IL-6 trans-signaling and is criti- cally involved in the development of colon cancer (68). In this disease, it has been suggested that shedding of sIL-6R from ade- nocarcinoma cells contributes to T cell survival and enhances the production of more IL-6 by T cells (66). Such findings sug- gest that IL-6 antagonists might be useful prophylactically or therapeutically for the treatment of humans with CAC. A recent study further demonstrated a novel form of IL-6 signaling. In MM cells that express high levels of IL-6Rα, IL-6Rα and the IGF1 receptor are recruited to lipid rafts following exposure of the cells to IL-6 (69). This facilitates hetero-oligomerization of both receptors and leads to JAK-independent activation of AKT, presumably via the IGF1 receptor (69). This type of cross-talk might provide a means for JAK-independent IL-6 signaling in tumor cell survival.
However, there is also evidence that IL-17 might be involved in tumor surveillance in immunocompetent mice (80). Therefore, current studies of the role of IL-17 in tumor development are still limited. Undoubtedly, it is necessary to determine whether the dominant function of IL-17 is in tumor promotion or tumor sur- veillance, and critical evaluation in appropriate mouse models of cancer using genetically altered animals lacking specific IL-17 or IL-17 receptor isoforms should address this issue.
IL-12 and IL-23 IL-12 and IL-23 belong to the IL-12 family of proinflammatory heterodimeric cytokines and are composed of IL-12p40/IL-12p35 and IL-12p40/IL-23p19 subunits, respectively (81). They are mainly produced by activated APCs and accessory cells such as DCs and phagocytes (82). The receptors for these cytokines are also heterodimeric — IL-12 binds an IL-12Rβ–IL-12Rβ2 het- erodimer, whereas IL-23 binds an IL-12Rβ1–IL-23R heterodimer (Figure 2) (81). The receptors for both IL-12 and IL-23 are mainly expressed on T cells, NK cells, and NKT cells. However, low lev- els of the receptor for IL-23 are also expressed on monocytes, macrophages, and DCs (82). Both cytokines activate TYK2 and JAK2 as well as STAT1, STAT3, STAT4, and STAT5 (81). Although IL-12 activates STAT4 most efficiently, IL-23 preferentially acti- vates STAT3 (Figure 2) (81). Despite the similarities in receptor subunit and signaling, recent studies have shown that IL-12 and IL-23 drive divergent immunological pathways and exert distinct effects on tumor development.
IL-17 Recently, a new T cell subset named “Th17,” characterized by the production of IL-17, was identified as an important player in inflammatory responses (Figure 3) (70). The production of IL-17 relies on STAT3 activation triggered by IL-23 (71). IL-17 induces the recruitment of immune cells to peripheral tissues, a response that requires NF-kB activation after IL-17 receptor engagement (Figure 2) (72, 73). IL-17 also leads to the induction of many proinflammatory factors, including TNF-α, IL-6, and IL-1β, sug-
Endogenous IL-12 is important for host resistance to tumors; the antitumor activity of IL-12 has been extensively reported in mouse models of cancer, where it has been shown to inhib- it tumorigenesis and induce regression of established tumors (82). The major antitumor activities of IL-12 rely on its ability to promote Th1 adaptive immunity and CTL responses (Figure 3) (82). IFN-γ produced by naive Th cells also contributes to the antitumor activity of IL-12. IFN-γ has both a direct toxic effect on cancer cells and antiangiogenic activity (82). The use of IL-12
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