Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms

Abstract

Objective. To evaluate the role of the MEK/ERK MAP kinase pathway in murine collagen-induced arthritis (CIA) using the selective MEK inhibitor PD184352. We examined the effects of the inhibitor in cytokine-stimulated synovial fibroblasts and in cytokine-induced arthritis in rabbits to investigate its antiinflammatory mechanisms.Methods. Murine CIA was used to assess the effects of the selective MEK inhibitor on paw edema, clinical scores, weight loss, histopathologic features, and joint levels of p-ERK. Western blotting and immunohistochemistry techniques were used to assess p-ERK in human and rabbit synovial fibroblasts and synovial tissue from rheumatoid arthritis (RA) patients. Interleukin-1␣ (IL-1␣)-stimulated stromelysin production in rabbit synovial fibroblasts was assessed by enzyme-linked immunosorbent assay. A rabbit IL-1␣-induced arthritis model was used to assess the effects of the inhibitor on IL-1␣-induced MEK activity, stromelysin production, and cartilage degradation.Results. In the CIA model, PD184352 inhibited paw edema and clinical arthritis scores in a dosedependent manner. Disease-induced weight loss and histopathologic changes were also significantly improved by treatment. Inhibition of disease-induced p-ERK levels in the joints was seen with the inhibitor. Levels of p-ERK in the synovium were higher in RA patients than in normal individuals. PD184352 reduced IL-1␣-induced p-ERK levels in human RA synovial fibroblasts. The production of p-ERK and stromelysin was also inhibited in IL-1␣-stimulated rabbit synovial fibroblasts. We observed IL-1␣-induced p-ERK in the synovial lining, subsynovial vasculature, and articular chondrocytes. IL-1␣-induced stromelysin production and proteoglycan loss from the articular cartilage were reduced by PD184352.Conclusion. These data demonstrate the inhibition of murine CIA by PD184352, support the hypothesis that antiinflammatory activity contributes to the mechanism of action of the inhibitor, and suggest that a selective inhibitor may effectively treat RA and other inflammatory disorders.

Inhibition of ERK MAPK Suppresses IL-23- and IL-1-Driven IL-17 Production and Attenuates Autoimmune Disease

“…Therefore, the effect of the ERK inhibitor suppresses innate cytokines that stimulate unconventional as well as conventional T cells. Our data clearly demonstrate that treatment with an ERK inhibitor reduces the severity of autoimmune disease in two EAE models, and this is consistent with its protective efficacy against collagen-induced arthritis (23). The ERK inhibitor prevented relapse when administered during remission in the relapsing-remitting model, but interestingly only had a significant protective effect in the acute MOG-induced model when administered during induction of EAE but not after development of disease.…”

“…EAE (1, 5, 10), collagen-induced arthritis (22), and experimental autoimmune uveitis (EAU) (14). Furthermore, inhibition of ERK can attenuate arthritis in mice, although the mechanism of suppression was not clear and its effect on Th17 responses were not examined (23). In this study, we examined if blocking ERK activation might attenuate the symptoms of EAE by suppressing the induction or expansion of autoantigen-specific T cells.…”

Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

“…Production of cytokines, including TNF␣, IL-6, IL-1␤, granulocyte-macrophage colony-stimulating factor, and RANTES, was inhibited by SNX-7081, with IC 50 values of Ͻ100 nM observed in several cases (Table 1). In LPS-stimulated THP-1 monocytes, potent inhibition of IL-1␤ and TNF␣ production (IC 50 33 nM and 61 nM, respectively) occurred after only 6 hours of SNX-7081 pretreatment. IL-8 inhibition was relatively weaker.…”

“…It is interesting to note that, while p38 has been a well-established therapeutic target for inflammation and RA, the RAF/ MEK/ERK pathway has been traditionally thought to be more relevant to oncology. However, MEK inhibition has also recently shown promise as a strategy for RA treatment (50). An Hsp90 inhibitor may be attractive in that different activated cell types in the RA phenotype may either preferentially use certain MAP kinase signaling pathways or make redundant use of them (2,44), so a general blockade of activated signaling would be preferred.…”

Reply

“…This was surprising and encouraging in light of the significant literature demonstrating the suppressive effects of MEK inhibition on a variety of leukocyte types in vitro, but, more importantly, illustrates that in vitro phenomena do not always translate to the whole organism. We were very interested to read the article by Wessels et al (1), which describes a clinical pharmacogenetic model that may predict response to methotrexate therapy in patients with recent-onset rheumatoid arthritis. The model incorporates sex, rheumatoid factor status, smoking status, Disease Activity Score, and 4 polymorphisms in the adenosine monophosphate deaminase (AMPD1), aminoimidazole carboxamide ribonucleotide transformylase (ATIC), inosine triphosphate pyrophosphatase (ITPA), and methylenetetrahydrofolate dehydrogenase (MTHFD1) genes.…”