RESUMO
Lymphotoxin beta receptor (LTßR) activation on mouse fibrosarcoma cells (BFS-1) results in enhanced solid tumor growth paralleled by increased angiogenesis induced by the expression of pro-angiogenic CXCL2. In our study, we demonstrate that both functional ligands of the LTßR, namely LTα(1) ß(2) and LIGHT, are involved in the activation of LTßR in solid fibrosarcomas. To identify whether the lymphocyte population is involved in the activation of LTßR in these fibrosarcoma tumors, we used conditional LTß-deficient mice that specifically lack LTß expression either on T cells (T-LTß(-/-)) or on B cells (B-LTß(-/-)). Solid tumor growth was reduced in both mouse strains when compared to tumor growth in wild-type mice, indicating the participation of both T and B host lymphocytes in the activation of LTßR in these tumors. Tumor growth was also reduced in LIGHT-deficient mice, suggesting a contribution of this ligand to the activation of LTßR in BFS-1 fibrosarcomas. LTßR signaling can involve IκBα and/or NFκB-inducing kinase (NIK) for subsequent NFκB activation in different types of cells. Expression of a dominant negative form of IκBα or of a dominant negative mutant of NIK resulted in decreased activation of NFκB signaling and reduced expression of pro-angiogenic CXCL2 in vitro. Moreover, expression of dominant negative form of NIK or an IκBα repressor in these fibrosarcoma cells resulted in reduced solid tumor growth in vivo, suggesting that both IκBα and NIK are involved in pro-angiogenic signaling after LTßR activation. Our data support the idea that the ablation of LTßR signaling should be considered for cancer treatment.
Assuntos
Fibrossarcoma/patologia , Heterotrímero de Linfotoxina alfa1 e beta2/metabolismo , Receptor beta de Linfotoxina/metabolismo , Linfotoxina-beta/fisiologia , NF-kappa B/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/fisiologia , Animais , Apoptose , Linfócitos B/metabolismo , Linfócitos B/patologia , Western Blotting , Proliferação de Células , Células Cultivadas , Quimiocina CXCL2/metabolismo , Feminino , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Emerging data indicate that alterations in the expression of tumour necrosis factor (TNF) superfamily members play a crucial role in the pathogenesis of intestinal inflammation. Recent results demonstrated that sustained transgenic expression of lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells (LIGHT; TNFSF14) induced severe intestinal inflammation, suggesting a specific role of LIGHT-mediated signalling to the intestinal compartment. In order to dissect the role of LIGHT in intestinal inflammation, we used LIGHT-deficient mice in the mouse model of acute dextran sodium sulphate-induced colitis. Interestingly, LIGHT-deficient mice were characterized by strongly reduced signs of intestinal inflammation compared with wild-type mice in this experimental model. Determination of mouse LIGHT mRNA expression in colon tissues of wild-type mice revealed a strong induction of mouse LIGHT mRNA expression during acute DSS-induced colitis. We therefore generated anti-mouse LIGHT monoclonal antibodies in LIGHT-deficient mice which bind specifically to LIGHT and are capable of neutralizing the activity of LIGHT in vitro and in vivo. With these antibodies, we demonstrated that neutralization of LIGHT during acute DSS-induced colitis resulted in reduced signs of intestinal inflammation. These data suggest that LIGHT is an important mediator in intestinal inflammation and may serve as a new target for therapeutic intervention.
