Suppression of Th1 and Th17 Responses and Induction of Treg Responses by IL-18-Expressing Plasmid Gene Combined with IL-4 on Collagen-Induced Arthritis.

objectivesIL-18 is a proinflammatory cytokine with multiple immunoregulatory properties. We studied the effect of IL-18 gene therapy on the development of murine collagen-induced arthritis (CIA).

methodsPlasmid pCAGGS-IL-18 along or in combination with IL-10 or IL-4 was administered to CIA mice. The incidence and severity of arthritis of the paws were determined by a visual scale. Joint destruction was determined by histology. The levels of a panel of cytokines and transcription factors in the synovium were determined by reverse transcription polymerase chain reaction and quantitative RT-PCR. Quantitative RT-PCR was employed to detect the mRNA expression of TLRs and their pathway on the surface of DCs.

resultsIL-18 gene therapy had no therapeutic effect on CIA mice. Additional coadministration with low dosage of recombinant IL-4 ameliorated the disease progression. Histopathological examination of the joints showed intact cartilage surface in IL-18 gene combined with IL-4-treated mice. The synovium of IL-18 gene combined with rIL4-treated mice had lower expression of TNF-

conclusionsOur findings indicate that pIL-18 gene combined with IL-4 ameliorates arthritis in the CIA mouse by suppression of Th1 and Th17 cytokines and increasing expression of FoxP3 and GATA-3. The plasmid backbone and multiple immunoregulatory properties of IL-18 appear to play a major role in the pIL-18 coadministration with rIL-4-mediated immunomodulation of arthritis through blocking the TLR2/MyD88/NF-kappa B signaling pathway.