Research On Immune Effect Characteristics Of Thrombopoietin On Cerebral Malaria And Its Related Mechanisms

Objective: Cerebral malaria(CM)is a threatening complication of Plasmodium falciparum infection,It seriously endangers human life and health.A large number of literatures point out that the pathogenesis of cerebral malaria may be related to platelet activation,excessive inflammatory reaction,activation of endothelial cells,and formation of microthrombus.Thus,how to reduce the occurrence of immunopathological damage may be the key to prevent and treat cerebral malaria.The current study has found that erythropoietin is great neuroprotective effect in the animal models of chemia,hypoxia,trauma and inflammation injury.In the animal model of cerebral malaria,the erythropoietin treatment in mice can reduce the occurrence of cerebral malaria,therefore,erythropoietin has an anti-CM effect.Thrombopoietin,as an important hematopoietic factor regulating the maturation and platelet production of megakaryocytes,it has a certain degree of homology with erythropoietin at the amino acid level.Our previous experimental results show that TPO can significantly inhibit the infection cerebral malaria for P.b ANKA C57BL/6 mouse by Intravenous injection TPO.as same as erythropoietin,thrombopoietin exerts a biological effect by binding to the ligand molecule c-Mpl.The current study found that not o nly megakaryocytes and platelets,but also in some immune cells express the ligand molecule,the immune cells have human polymorphonuclear cells,dendritic cells,neutrophils And so on,and to a certain extent,affect the cellular immune function.Therefore,based on the previous work,this study aims to further study the immunomodulatory effects of Thrombopoietin on cerebral malaria and try to find out the possible mechanism by which Thrombopoietin inhibits the occurrence of cerebral malaria,thus providing a new explanation for the characteristics of Thrombopoietin and the treatment of cerebral malaria Theoretical basis.Methods: To establish a C57BL/6 mouse model of infection with P.b ANKA,we investigate the effect of TPO on dendritic cells,immune response and NF-κB pathway in spleen of infected mice.DC2.4 cell line is cultured in vitro,the effect of TPO is observed by flow cytometry,ELISA and Real-time PC R under the action of LPS and / or TPO to observe the changes of dendritic cells and NF-κB pathway of the changes,and observe the expression of c-Mpl.Results: In the Pb.ANKA-infected C57 BL / 6 mouse model,we find:a.Thrombopoietin can inhibit the occurrence of cerebral malaria in infected mice;b.Thrombopoietin can inhibit the proliferation of dendritic cells in infected spleen;c.Thrombopoietin decreased the expression of proinflammatory and proinflammatory cytokines d.in the spleens of infected mice;e.Thrombopoietin can influence the expression of NF-κB pathway.In LPS stimulated DC2.4 cell mode l,we find: a.Thrombopoietin inhibited the relative expression of TLR4 m RNA in dendritic cells;b.Thrombopoietin inhibits the maturation of dendritic cells;c.Thrombopoietin reduces the level of inflammatory cytokines d.Thrombopoietin inhibits the expression of c-Mpl in dendritic cells.Conclusion: In infected C57 BL / 6 mice,TPO can inhibit the occurrence of cerebral malaria in infected mice by inhibiting the proliferation of dendritic cells and reducing the levels of Th1-type and proinflammatory cytok ines.In vitro experiments,TPO can reduce DC2.4 cells TLR4 expression,while inhibiting the secretion of related inflammatory cytokines.This may be related to the role of TPO in DC2.4 c-Mpl,thereby inhibiting the activation of NF-κB intracellular signaling pathways.