Efeito do imunomodulador P-MAPA associado à interleucina-12 no carcinoma de ovário de ratas Fischer 344: abordagem do processo inflamatório e sistema imune
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2020-02-21
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Universidade Estadual Paulista (Unesp)
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O câncer de ovário (CO) é a segunda mais letal de todas as neoplasias ginecológicas e muitas mulheres adquirem quimiorresistência associada ao processo inflamatório. A interleucina-12 (IL-12) é responsável pela resposta inflamatória T helper 1 (Th1) e o agregado proteico de fosfolinoleato de amônio e magnésio e anidrido palmitoleato (P-MAPA) atua como um agente imunoestimulador em cânceres agressivos. Este estudo investigou os tratamentos funcionais com P-MAPA e IL-12 no processo inflamatório e nas células imunes relacionadas ao CO em um modelo in vivo. O CO foi induzido quimicamente com 7,12-dimetilbenz(a)antraceno (DMBA) diretamente na bolsa ovariana e, após o desenvolvimento dos tumores, os animais receberam P-MAPA, IL-12 ou P-MAPA combinado com IL-12. A terapia combinatória melhorou as características histológicas características do CO, contribuindo para a redução das células inflamatórias, acúmulo de adipócitos, além de apresentar um tecido mole e móvel, sem aderências e implantes peritoneais. O tratamento com P-MAPA aumentou os níveis de TLR2, TLR4 e TRIF nos OCs, enquanto diminuiu o número de células T reguladoras (Treg) (CD4+ CD25+/FoxP-3+ e CD8+ FoxP-3+). Além disso, a associação de P-MAPA com IL-12 estimulou significativamente as células T CD4+ e CD8+ efetoras nos linfonodos drenantes. Em relação aos mediadores inflamatórios, o P-MAPA aumentou o nível da citocina pró-inflamatória IL-17, enquanto o P-MAPA+IL-12 aumentou os níveis de IL-1β. O tratamento com IL-12 aumentou os níveis das citocinas IL-17, TNF-α, IL-1β e IL-2 e a quimiocina MIP-1α. Concluímos que o P-MAPA regulou positivamente a sinalização de TLR2 e TLR4, possivelmente ativando a via não-canônica, estimulando a resposta imune frente ao tumor. A terapia combinada melhorou a resposta efetiva das células T, contribuindo assim para eliminar as células tumorais. Essas imunoterapias representam uma contribuição adicional para o tratamento da CO.
Ovarian cancer (OC) is the second most lethal among gynecological malignancies and many women acquire chemoresistance associated with the inflammatory process. Interleukin-12 (IL-12) is responsible for the inflammatory T helper 1 (Th1) response and the protein aggregate of ammonium and magnesium phospholinoleate and palmitoleate anhydride (P-MAPA) acts as an immunostimulatory agent in aggressive cancers. This study investigated the functional treatments with P-MAPA and IL-12 on the inflammatory process and on the OC-related immune cells in an in vivo model. OCs were chemically induced with 7,12-dimethylbenz(a)anthracene (DMBA) into the ovarian bursa, and after developing tumors, the animals were given P-MAPA, IL-12, or P-MAPA combined with IL-12. The combinatory therapy improved the general features of OC, contributing to a reduction in the inflammatory cells, adipocyte accumulation in addition to revealing a soft and mobile tissue with no adherences and peritoneal implants. P-MAPA treatment increased the levels of TLR2, TLR4 and TRIF in OCs while decreased the number of T regulatory (Treg) cells (CD4+CD25+/FoxP-3+ and CD8+FoxP-3+). Additionally, the association of P-MAPA with IL-12 significantly stimulated the CD4+ and CD8+ T cell effector in draining lymphnodes. Regarding to the inflammatory mediators, P-MAPA enhanced the levels of pro-inflammatory cytokine IL-17 while P-MAPA+IL-12 increased IL-1β levels. The IL-12 treatment enhanced IL-17, TNF-α, IL-1β and IL-2 cytokines levels and the chemokine MIP-1α. We conclude that P-MAPA upregulated TLR2 and TLR4 signaling, possibly activating the non-canonical pathway, while attenuating the tumor immunosuppression. Combinatory therapy improved the effector T cell response, thereby contributing to eliminate tumor cells. These immunotherapies represent an additional contribution for the treatment of OC.
Ovarian cancer (OC) is the second most lethal among gynecological malignancies and many women acquire chemoresistance associated with the inflammatory process. Interleukin-12 (IL-12) is responsible for the inflammatory T helper 1 (Th1) response and the protein aggregate of ammonium and magnesium phospholinoleate and palmitoleate anhydride (P-MAPA) acts as an immunostimulatory agent in aggressive cancers. This study investigated the functional treatments with P-MAPA and IL-12 on the inflammatory process and on the OC-related immune cells in an in vivo model. OCs were chemically induced with 7,12-dimethylbenz(a)anthracene (DMBA) into the ovarian bursa, and after developing tumors, the animals were given P-MAPA, IL-12, or P-MAPA combined with IL-12. The combinatory therapy improved the general features of OC, contributing to a reduction in the inflammatory cells, adipocyte accumulation in addition to revealing a soft and mobile tissue with no adherences and peritoneal implants. P-MAPA treatment increased the levels of TLR2, TLR4 and TRIF in OCs while decreased the number of T regulatory (Treg) cells (CD4+CD25+/FoxP-3+ and CD8+FoxP-3+). Additionally, the association of P-MAPA with IL-12 significantly stimulated the CD4+ and CD8+ T cell effector in draining lymphnodes. Regarding to the inflammatory mediators, P-MAPA enhanced the levels of pro-inflammatory cytokine IL-17 while P-MAPA+IL-12 increased IL-1β levels. The IL-12 treatment enhanced IL-17, TNF-α, IL-1β and IL-2 cytokines levels and the chemokine MIP-1α. We conclude that P-MAPA upregulated TLR2 and TLR4 signaling, possibly activating the non-canonical pathway, while attenuating the tumor immunosuppression. Combinatory therapy improved the effector T cell response, thereby contributing to eliminate tumor cells. These immunotherapies represent an additional contribution for the treatment of OC.
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Palavras-chave
Câncer de ovário, P-MAPA, IL-12, TLR, inflamação, Células imunes, Ovarian cancer, Immune cells, Inflammation