Regulation of Interleukin-1β-induced Interleukin-6 Gene Expression in Human Fibroblast-like Synoviocytes by p38 Mitogen-activated Protein Kinase

Abstract

Involvement of p38 mitogen-activated protein (MAP) kinase in interleukin (IL)-6 gene expression of human fibroblast-like synoviocytes (FLSs) was assessed. p38 MAP kinase was constitutively expressed in human FLSs and activated in response to IL-1␤. A pyridinylimidazole compound, SB203580, inhibited p38 MAP kinase activity in vivo, since the activity of MAPKAP kinase-2 (a substrate of p38 MAP kinase) in IL-1␤-stimulated FLSs was totally suppressed by it. SB203580 concentrationdependently inhibited protein production and gene expression of IL-6 by human FLSs. The effect of SB203580 was dependent on de novo protein synthesis. SB203580 significantly reduced the stability of IL-6 mRNA without affecting the rate of IL-6 gene transcription. Here, we provide evidence that p38 MAP kinase is activated in response to IL-1␤ in human FLSs and is involved in IL-6 synthesis by stabilizing IL-6 mRNA.

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

“…There are several other reports that suggest the relevance of MAPK activation to the immunopathogenesis of RA (48)(49)(50)(51)(52). However, no report has described the effects of MAPK pathway inhibitors on the ex vivo cytokine production by freshly isolated synovial cells from RA patients.…”

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

“…Relatively little is known about the signaling pathways responsible for IL-6 mRNA stabilization. It has been found by multiple groups that the mitogen-activated protein kinase (MAPK) p38 stabilizes IL-6 mRNA [12,[15][16][17][18]. Another kinase often associated with mRNA stabilization is protein kinase C (PKC).…”

“…It has been shown that IL-1β stabilizes multiple mRNA species, including IL-6, in a variety of cell types [9,12,14,16,35,36]. A paradigm commonly used to study effects on mRNA stabilization is the blockade of new transcription by a transcriptional inhibitor, such as actinomycin D, followed by quantification of the mRNA levels at several time points after inhibition of transcription [37].…”

“…Importantly, both can be activated by IL-1β and have been convincingly implicated in COX-2 mRNA stabilization [21,31,[41][42][43][44][45][46]. Moreover, in multiple studies, IL-1β-induced mRNA stabilization of IL-6 was shown to be crucially dependent on p38 [12,16], whereas dependence on PKC has not yet been described. Therefore, we used pharmacological inhibitors of p38 and PKC to investigate if they are involved in the mRNA-stabilizing effect of IL-1β in our experimental system.…”

“…In several systems, IL-6 has been described to have a short half life, varying from 30 minutes [8][9][10]] to 50 minutes [11]. Several extracellular stimuli have been described to have a stabilizing effect on IL-6 mRNA, such as IL-1β [9,12]; IL-17 [13,14];…”