Combinations of ERK and p38 MAPK Inhibitors Ablate Tumor Necrosis Factor-α (TNF-α) mRNA Induction

Abstract

Tumor necrosis factor-␣ (TNF-␣) is a potent proinflammatory cytokine whose synthesis and secretion are implicated in diverse pathologies. Hence, inhibition of TNF-␣ transcription or translation and neutralization of its protein product represent major pharmaceutical strategies to control inflammation. We have studied the role of ERK and p38 mitogen-activated protein (MAP) kinase in controlling TNF-␣ mRNA levels in differentiated THP-1 cells and in freshly purified human monocytes. We show here that it is possible to produce virtually complete inhibition of lipopolysaccharidestimulated TNF-␣ mRNA accumulation by using a combination of ERK and p38 MAP kinase inhibitors. Furthermore, substantial inhibition is achievable using combinations of 1 M of each inhibitor, whereas inhibitors used individually are incapable of producing complete inhibition even at high concentrations. Finally, addressing mechanisms involved, we show that inhibition of p38 MAP kinase selectively destabilizes TNF-␣ transcripts but does not affect degradation of c-jun transcripts. These results impinge on the controversy in the literature surrounding the mode of action of MAP kinase inhibitors on TNF-␣ mRNA and suggest the use of combinations of MAP kinase inhibitors as an effective anti-inflammatory strategy.Monocytes and macrophages play a pivotal role in inflammation and immune regulation. Upon activation, monocytes produce and release many inflammatory mediators such as IL-1, 1

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

“…Ex vivo production of TNF␣ and IL-1␤ was further suppressed by the presence of both kinase inhibitors. The requirement for the inhibition of both ERK and p38 MAPK pathways for the strong suppression of LPS-induced TNF␣ production (40,53) is consistent with our data.…”

“…Several investigators demonstrated that PD98059, an inhibitor of MEK, suppressed TNF␣ production in LPS-stimulated or CD154-stimulated monocytes (36)(37)(38)(39). Conversely, it has been reported that p38 is involved not only in the translation, but also in the stabilization of TNF␣ mRNA (40)(41)(42). These findings are in accordance with the results of the present study, that activation of both ERK and p38 is important for TNF␣ production by CD154 plus IFN␥-stimulated CD14ϩ synovial cells and for ex vivo TNF␣ production by freshly isolated synovial cells from RA patients.…”

Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

“…As previously reported, all three MAPK signaling pathways (ERK, JNK, and p38 MAPK) are involved in the transcription of TNF-a mRNA after LPS induction, and activation of each MAPK signal leads to full induction of the TNF-a gene. [52][53][54] Based upon two aspects of our present results, we suggest that ERK and p38 MAPK are pivotal signaling events in the mediation of DcR3 response. First, MEK inhibitors (PD98059 and U0126) and a p38 MAPK inhibitor (SB203580) can inhibit DcR3-elicited TNF-a synthesis and osteoclast formation.…”

Identification and Characterization ofChlamydia pneumoniae-Specific Proteins That Activate Tumor Necrosis Factor Alpha Production in RAW 264.7 Murine Macrophages

“…In contrast, the effect of LPS on stimulation of TNF-␣ expression in RAW 264.7 cells was not affected by U0126. These findings are consistent with reports demonstrating that in addition to ERK 1/2, LPS-induced TNF-␣ expression occurs via p38 (2,45) and JNK (3,29) signaling. In contrast, C. pneumoniae antigens did not activate JNK and p38 kinases in this study (Fig.…”