IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice: is the effect mediated by the CpG signaling TLR9?
IL-18 regulates either Th1 or Th2 responses depending on the cytokine microenvironment. Administration of recombinant IL-18 (rIL-18) alone does not promote Th1 response, but rather induces Th2 response and exacerbates Leishmania major infection in susceptible BALB/c mice. Here, we treated BALB/c mice with an IL-18-expressing plasmid by using a gene gun weekly after L. major infection. This gene therapy resulted in improved pathogenic process and preferential induction of Th1 responses by inducing the expression of IL-12 p40, but treatment with rIL-18 did not. Notably, simultaneous administration of rIL-18 with an empty plasmid vector rendered BALB/c mice resistant to the infection, despite the fact that treatment with either rIL-18 alone or the plasmid vector alone did not influence the susceptibility. The synergistic role of the vector with rIL-18 was found to depend on CpG motifs, which enhanced expression of proinflammatory cytokines, especially IL-12, from APCs through Toll-like receptor (TLR) 9 ligation. Treatment with methylated plasmid vector in which CpG was disrupted could no longer prevent the disease development in coadministration with rIL-18. Taken together, IL-18 gene therapy was shown to develop Th1-type protective immunity in L. major-infected BALB/c mice without the requirement of exogenous IL-12, probably via CpG-TLR9 signaling pathway.
Li
Y
Y
Department of Microbiology and Immunology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ishii
K
K
Hisaeda
H
H
Hamano
S
S
Zhang
M
M
Nakanishi
K
K
Yoshimoto
T
T
Hemmi
H
H
Takeda
K
K
Akira
S
S
Iwakura
Y
Y
Himeno
K
K
D000818:Animals; D019470:Biolistics; D018899:CpG Islands; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D016233:Immunotherapy, Active / Q000379:methods*; D018664:Interleukin-12 / Q000276:immunology; D020382:Interleukin-18 / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology*; D051217:Toll-Like Receptor 9
D004268:DNA-Binding Proteins; D020382:Interleukin-18; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D018664:Interleukin-12