title: TLR4-mediated activation of MyD88 signaling induces protective immune response and IL-10 down-regulation in Leishmania donovani infection.
abstract: In visceral leishmaniasis, a fragmentary IL-12 driven type 1 immune response along with the expansion of IL-10 producing T-cells correlates with parasite burden and pathogenesis. Successful immunotherapy involves both suppression of IL-10 production and enhancement of IL-12 and nitric oxide (NO) production. As custodians of the innate immunity, the toll-like receptors (TLRs) constitute the first line of defense against invading pathogens. The TLR-signaling cascade initiated following innate recognition of microbes shapes the adaptive immune response. Whereas numerous studies have correlated parasite control to the adaptive response in Leishmania infection, growing body of evidence suggests that the activation of the innate immune response also plays a pivotal role in disease pathogenicity. In this study, using a TLR4 agonist, a Leishmania donovani (LD) derived 29 kDa β 1,4 galactose terminal glycoprotein (GP29), we demonstrated that the TLR adaptor myeloid differentiation primary response protein-88 (MyD88) was essential for optimal immunity following LD infection. Treatment of LD-infected cells with GP29 stimulated the production of IL-12 and NO while suppressing IL-10 production. Treatment of LD-infected cells with GP29 also induced the degradation of IKB and the nuclear translocation of NF-κB, as well as rapid phosphorylation of p38 MAPK and p54/56 JNK. Knockdown of TLR4 or MYD88 using siRNA showed reduced inflammatory response to GP29 in LD-infected cells. Biochemical inhibition of p38 MAPK, JNK or NF-κB, but not p42/44 ERK, reduced GP29-induced IL-12 and NO production in LD-infected cells. These results suggested a potential role for the TLR4-MyD88-IL-12 pathway to induce adaptive immune responses to LD infection that culminated in an effective control of intracellular parasite replication.
authors.forename: Joydeep
authors.initials: J
authors.lastname: Paul
authors.forename: Kshudiram
authors.initials: K
authors.lastname: Naskar
authors.forename: Sayan
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Md Nur
authors.initials: MN
authors.lastname: Alam
authors.forename: Tapati
authors.initials: T
authors.lastname: Chakraborti
authors.forename: Tripti
authors.initials: T
authors.lastname: De
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D007893:Leishmania donovani / Q000201:enzymology / Q000276:immunology; D007896:Leishmaniasis / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10