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

Abstract

Objectives IL-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). Methods Plasmid 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. Results IL-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-α, IFN-γ, and IL-17 and higher expression of IL-10. The mechanism of this response appeared to involve modulation of transcription factors FoxP3 and GATA-3. The DCs in the spleen and lymph nodes of IL-18 gene combined with rIL4-treated mice had lower expression of TLR2, MyD88, and NF-kB. Conclusions Our 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.

Brown adipose tissue ameliorates autoimmune arthritis via inhibition of Th17 cells

“…Ex vivo flow cytometry and immunofluorescence staining analyses showed that the populations of Foxp3 + Treg cells did not significantly differ among groups. However, the population of Th17 cells was significantly www.nature.com/scientificreports/ model 47,48 . In this study, Th1 cells were determined by flow cytometry in each mouse groups, there were no significant differences respectively (data not shown).…”

TlR2 and TlR4 are involved in the treatment of rheumatoid arthritis synovial fibroblasts with a medicated serum of asarinin through inhibition of Th1/Th17 cytokines

“…TNF-α, IFN-γ, IL-6 and IL-17A were also expressed in OA synovial cells, but TNF-α, IFN-γ, IL-6 and IL-17A expression was low and no significant differences were observed before and after asarinin treatment. IFN-γ, IL-6, TNF-α and IL-17A are inflammatory cytokines and IFN-γ and TNF-α are T h 1-type cytokines (6). IL-6 is also the main inflammatory factor in RA joint inflammation, but its pathogenic effect is different from that of IL-1 and TNF-α, which mainly induces the production of immunoglobulins and the formation of acute phase proteins (37)(38)(39)(40).…”

“…Although T h 2 cells secrete IL-6, IL-6 still serves a role as an inflammatory cytokine. Additionally, T h 17 cells secrete IL-17, which is generally considered an important inflammatory mediator that modulates local infiltration and tissue injury of inflammatory cells by inducing the expression of other inflammatory cytokines, such as IL-6 and TNF-α, and chemokines, such as monocyte chemotactic protein 1 and macrophage inflammatory protein-2 (1,6). Mice deficient in IL-17 exhibit reduced severity of arthritis, and mice with increased IL-17 levels exhibit exacerbated levels of the disease (41,42).…”

“…It has become clear in the last few years that T cell-derived cytokines expressed preferentially by T h 1 cells contribute to joint destruction and inflammatory response in RA, whereas T h 2 cell-associated cytokines may be protective (2,3). However, recent research on T h 17 cells and regulatory T cells (Treg) has demonstrated that an imbalance between T h 1/T h 2/T h 17/Treg cells is important to the pathogenesis of RA (4)(5)(6). Although the origin of RA is unclear, it has been determined that lymphocytes accumulate around the terminal blood vessels of the subsynovial layer prior to the inflammatory response (7).…”

Amelioration of CIA by Asarinin Is Associated to a Downregulation of TLR9/NF-κB and Regulation of Th1/Th2/Treg Expression

“…34) OX-40 is originally thought to be a surface marker activation of CD4 + T cells in rats, 35) which is mainly induced at the effector stage of T cells and is mainly expressed on Th2 cells. 36) Dendritic cells express TLR9 in cells and specifically identify non-methylated CpG motifs, which has been shown to promote Th1 immune responses in L. major-infected susceptible mice. TLR9 promotes the expression of inflammatory cytokines by activating NF-κB.…”