RESUMO
Deregulated Toll-like receptor (TLR)-triggered inflammatory responses that depend on NF-κB are detrimental to the host via excessive production of proinflammatory cytokines, including TNF-α. Stat2 is a critical component of type I IFN signaling, but it is not thought to participate in TLR signaling. Our study shows that LPS-induced lethality in Stat2(-/-) mice is accelerated as a result of increased cellular transmigration. Blocking intercellular adhesion molecule-1 prevents cellular egress and confers survival of Stat2(-/-) mice. The main determinant of cellular egress in Stat2(-/-) mice is the genotype of the host and not the circulating leukocyte. Surprisingly, lethality and cellular egress observed on Stat2(-/-) mice are not associated with excessive increases in classical sepsis cytokines or chemokines. Indeed, in the absence of Stat2, cytokine production in response to multiple TLR agonists is reduced. We find that Stat2 loss leads to reduced expression of NF-κB target genes by affecting nuclear translocation of NF-κB. Thus, our data reveal the existence of a different mechanism of LPS-induced lethality that is independent of NF-κB triggered cytokine storm but dependent on cellular egress.
Assuntos
Núcleo Celular/metabolismo , Citocinas/biossíntese , Lipopolissacarídeos/toxicidade , NF-kappa B/metabolismo , Fator de Transcrição STAT2 , Sepse/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Animais , Núcleo Celular/genética , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/genética , Sepse/induzido quimicamente , Sepse/genética , Sepse/patologia , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMO
The role of STAT2 in mediating the antigrowth effects of type I interferon (IFN) is well-documented in vitro. Yet evidence of IFN-activated STAT2 as having tumor suppressor function in vivo and participation in antitumor immunity is lacking. Here we show in a syngeneic tumor transplantation model that STAT2 reduces tumor growth. Stat2(-/-) mice formed larger tumors compared to wild type (WT) mice. IFN-ß treatment of Stat2(-/-) mice did not cause tumor regression. Gene expression analysis revealed a small subset of immunomodulatory genes to be downregulated in tumors established in Stat2(-/-) mice. Additionally, we found tumor antigen cross-presentation by Stat2(-/-) dendritic cells to T cells to be impaired. Adoptive transfer of tumor antigen specific CD8(+) T cells primed by Stat2(-/-) dendritic cells into tumor-bearing Stat2(-/-) mice did not induce tumor regression with IFN-ß intervention. We observed that an increase in the number of CD4(+) and CD8(+) T cells in the draining lymph nodes of IFN-ß-treated tumor-bearing WT mice was absent in IFN-ß treated Stat2(-/-) mice. Thus our study provides evidence for further evaluation of STAT2 function in cancer patients receiving type I IFN based immunotherapy.