A Novel Mechanism for TNF-α Regulation by p38 MAPK: Involvement of NF-κB with Implications for Therapy in Rheumatoid Arthritis

Abstract

TNF-α is a key factor in a variety of inflammatory diseases. This study examines the role of p38 MAPK in the regulation of TNF-α in primary human cells relevant to inflammation, e.g., macrophages and rheumatoid synovial cells. Using a dominant negative variant (D168A) of p38 MAPK and a kinase inhibitor, SB203580, we confirm in primary human macrophages that p38 MAPK regulates TNF-α production using a posttranscriptional mechanism requiring the 3′ untranslated region of the gene. However, in LPS-activated primary human macrophages we also detect a second previously unidentified mechanism, the p38 MAPK modulation of TNF-α transcription. This is mediated through p38 MAPK regulation of NF-κB. Interestingly this mechanism was not observed in rheumatoid synovial cells. Importantly however, the dominant negative mutant of p38 MAPK, but not SB203580 was effective at inhibiting spontaneous TNF-α production in these ex vivo rheumatoid synovial cell cultures. These data indicate there are potential major differences in the role of p38 MAPK in inflammatory signaling that have a bearing on the use of this kinase as a target for therapy. These results indicate despite disappointing results with p38 MAPK inhibitors in the clinic, this kinase is a valid target in rheumatoid disease.

Zinc Signals Are Essential for Lipopolysaccharide-Induced Signal Transduction in Monocytes

“…In this experimental system the p38 MAPK inhibitor SB202910 did not affect synthesis of TNF-␣ protein, but posttranslational events, presumably processing or secretion of the precursor protein. Other groups have found that p38 MAPK is either involved in TNF-␣ transcription through regulation of NF-B, or translational control of TNF-␣ expression, or mRNA stability (41)(42)(43). Because chelation of zinc signals with TPEN leads to a decrease in NF-B activity and mRNA synthesis, this result is a sign.…”

Interleukin-10 inhibits tumor necrosis factor-α production in lipopolysaccharide-stimulated RAW 264.7 cells through reduced MyD88 expression

“…The MyD88-dependent pathway regulates activation of NF-κB, p38 and SAPK/JNK for TNF-α production. [12][13][14] Therefore, the effect of IL-10 on the expression of MyD88 protein and mRNA was examined in LPS-stimulated RAW 264.7 cells (Fig. 3).…”

Single doses of p38 MAP kinase inhibitors or prednisolone affect CRP and IL-6 in patients with active Rheumatoid Arthritis (RA)

“…p38 mitogen-activated protein kinase (MAPK) is a serine/threonine-directed protein kinase which phosphorylates a number of intracellular signal transduction molecules that are involved in regulating the biosynthesis of inflammatory cytokines [9]. Consequently, inhibitors of this kinase, were expected to be effective in diseases where the pro-inflammatory mechanisms are cytokinedependent such as rheumatoid arthritis.…”