Differential Effects of IL-1α and IL-1β on Tumorigenicity Patterns and Invasiveness

Abstract

In this study, we show that distinct compartmentalization patterns of the IL-1 molecules (IL-1α and IL-1β), in the milieu of tumor cells that produce them, differentially affect the malignant process. Active forms of IL-1, namely precursor IL-1α (pIL-1α), mature IL-1β (mIL-1β), and mIL-1β fused to a signal sequence (ssIL-1β), were transfected into an established fibrosarcoma cell line, and tumorigenicity and antitumor immunity were assessed. Cell lines transfected with pIL-1α, which expresses IL-1α on the membrane, fail to develop local tumors and activate antitumor effector mechanisms, such as CTLs, NK cells, and high levels of IFN-γ production. Cells transfected with secretable IL-1β (mIL-1β and ssIL-1β) were more aggressive than wild-type and mock-transfected tumor cells; ssIL-1β transfectants even exhibited metastatic tumors in the lungs of mice after i.v. inoculation (experimental metastasis). In IL-1β tumors, increased vascularity patterns were observed. No detectable antitumor effector mechanisms were observed in spleens of mice injected with IL-1β transfectants, mock-transfected or wild-type fibrosarcoma cells. Moreover, in spleens of mice injected with IL-1β transfectants, suppression of polyclonal mitogenic responses (proliferation, IFN-γ and IL-2 production) to Con A was observed, suggesting the development of general anergy. Histologically, infiltrating mononuclear cells penetrating the tumor were seen at pIL-1α tumor sites, whereas in mIL-1β and ssIL-1β tumor sites such infiltrating cells do not penetrate inside the tumor. This is, to our knowledge, the first report on differential, nonredundant, in vivo effects of IL-1α and IL-1β in malignant processes; IL-1α reduces tumorigenicity by inducing antitumor immunity, whereas IL-1β promotes invasiveness, including tumor angiogenesis, and also induces immune suppression in the host.

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

“…On the contrary, the membrane IL-1α even slightly protected the mice from CCl 4 -induced acute liver injury. It has been suggested that membrane IL-1α could function as an adhesion molecular to promote immune responses [11,50]. The mechanism of its protective role in acute liver injury still needs further investigation.…”

Host-Derived Interleukin-1α Is Important in Determining the Immunogenicity of 3-Methylcholantrene Tumor Cells

“…Alternatively, small amounts of IL-1␣, which is homeostatically expressed in cells, but not secreted, can be poured out from necrotizing cells at the site of carcinogen injection, and serve as a "danger signal" for mounting antitumor cells immunity (46). In contrast, IL-1␤ is only active as a secreted molecule, which is not accumulated in the producing cell; upon secretion, it possibly induces potent and widespread inflammatory responses that override, or even suppress, manifestations of adaptive immunity (21)(22)(23)(24)(25). In experimental models of autoimmune diseases, similar involvement of Th1 and Th17 cells, in induction and perpetuation of the pathogenic inflammatory responses, has been demonstrated.…”

“…IL-1␤ is only active in its mature secretable form and is thus a good inducer of extensive inflammatory responses. Indeed, we and others have shown that IL-1␤, secreted by malignant cells or host cells in the tumor's microenvironment, contributes to increased tumor invasiveness, tumor angiogenesis and tumor-mediated suppression (21)(22)(23)(24)(25)(26). IL-1␣, in addition to its secreted mature form, is also active in cellassociated forms, i.e., the whole precursor molecule, the pro-piece, which is derived following cleavage of the precursor by calpain, and the functional membrane-associated form.…”

IL-1B −31T>C promoter polymorphism is associated with gastric stump cancer but not with early onset or conventional gastric cancers

“…It has been reported that carriers of the IL-1B −31C allele, showed higher plasmatic concentrations of IL-1B than subjects with wild-type IL-1B genotype [14]. Upregulation of IL-1B is involved in tumor-promoting effects such as invasiveness [40], angiogenesis [38], and metastasis [45] and has been recognized as negative prognostic factor, mainly in metastatic cancer [27]. Conversely, an association between peptic ulcer and the IL-1B −31T polymorphism has been described [8,9].…”