Inhibition of pro-inflammatory cytokine production by the dual p38/JNK2 inhibitor BIRB796 correlates with the inhibition of p38 signaling

Characterization of a murine keyhole limpet hemocyanin (KLH)-delayed-type hypersensitivity (DTH) model: Role for p38 kinase

“…These findings suggest the efficacy of BIRB-796 in the KLH-DTH model primarily being the consequence of inhibition of p38 kinase activity rather than dual inhibition of p38 and JNK activity as postulated previously [33,41,54]. Our data is in agreement with the recent data from Gruenbaum et al [55] suggesting that 1) the anti-inflammatory activity of BIRB-796 in vivo correlates with inhibition of p38 activity despite BIRB-796 being a dual p38/JNK2 kinase inhibitor in molecular assays and 2) BIRB-796 appears to be at least 100 fold selective for p38 functional activity versus JNK activity.…”

“…Although IL-10 has been proposed to be a negative regulator of the DTH response [64][65][66], the decreased levels in BIRB-796-treated mice may not be unexpected. BIRB-796 inhibits IL-1β and TNFα, which have been shown to modulate IL-10 levels [67], and recent data indicates that p38 kinase modulates IL-10 expression in macrophages [68] and peripheral blood mononuclear cells [55]. These data are consistent with prior studies indicating a role for p38 kinase in the regulation of IL-1β and IL-10 in vitro and in vivo [34,67].…”

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

“…However, this finding is in line with previously published results. Cogan et al [46] demonstrated an IC 50 for 780 nM for BIRB-796 in human whole blood in contrast to an IC 50 of 7.6 nM found in human PBMCs by Gruenbaum et al [47]. Hence, caution needs to be exercised when interpreting data from whole blood assays and assays performed with primary cells.…”

The as-yet unfulfilled promise of p38 MAPK inhibitors

“…interest ingly, vX-702 is clinically efficacious in patients with acute coro nary syndrome post-catheterization, 5 and in vitro BirB796 treatment decreases lipopolysaccharide-induced production of proinflammatory cyto kines by peripheral blood mononuclear cells. 6 one potential explanation for the disappointing results in ra is that p38α inhibition decreases these examples of acute inflammation better than it does the more-chronic type of inflammation encountered in ra. another possibility is that the p38 inhibitors are subject to doselimited efficacy secondary to drug toxicity, as with the first-generation compound BirB796.…”

“…the p38 maPKs might mediate anti-inflammatory effects through il-10, which decreases the production of proinflammatory cytokines, including tnF and interferon γ. in a study mentioned earlier, 6 pre-treatment with BirB796 signifi cantly decreased il-10 production by lipopolysaccharide-st imulated peripheral blood mononuclear cells. in addition to its effects via il-10, the relative actions of p38 are likely to be specific to cell lineage and micro environment.…”