p38 inhibition and not MK2 inhibition enhances the secretion of chemokines from TNF-α activated rheumatoid arthritis fibroblast-like synoviocytes.

Objectives For many years the p38 MAP kinase (MAPK) has been a major anti-inflammatory target for the development of an oral therapy for rheumatoid arthritis (RA). However, disappointing results from Phase II clinical studies suggest that adaptations may occur, which allow escape from blockade of the p38 pathway. In this study we investigated whether p38 inhibition mediated JNK activation represents such an escape mechanism. Methods Interaction between the JNK and p38 pathways was studied in TNF-alpha stimulated THP-1 monocytes, primary macrophages and fibroblast-like synoviocytes from OA and RA patients using pharmacological inhibitors and siRNAs. Results TNF-alpha induced phosphorylation of JNK and c-Jun was sustained by p38 inhibitors in monocytes, primary macrophages and FLS. Upregulation of Mip1 alpha, Mip1 beta and IL-8 mRNAs and protein were observed upon p38 inhibition. More importantly, inhibition of MK2, the substrate of p38 did not sustain JNK activation upon TNF-alpha activation and did not elevate Mip1 alpha, Mip1 beta and IL-8 chemokines as compared to TNF-alpha alone. In this study, TNF-alpha or IL-1 beta induced JNK activation is sustained by p38 inhibition, resulting in enhanced chemokine secretion. Conclusion Based on the suggested role of these chemokines in RA pathogenesis, the upregulation of these chemokines may provide an explanation for the lack of efficacy of p38 inhibitors in Phase II. The absence of any effect of MK2 inhibition in our models on this mechanism, while coming with similar efficacy on blocking p38, provides support for further investigations to reveal the potential of MK2 inhibition as a novel treatment of RA.