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

Abstract

Background/Aims: Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) is promising for the treatment of inflammatory disorders, however, the efficacy of p38 MAPK inhibitors in clinical trials is limited so far. Since functional sensitivity of p38 MAPK is commonly predicted by preclinical species, we systematically investigated interspecies differences including human tissue. Methods: Ex vivo test models were established using whole blood and primary cells from different species such as mice, rats, pigs and humans to compare LPS-induced TNF-α inhibition of four different p38 MAPK reference inhibitors SB 203580, BIRB-796, Pamapimod, and a Losmapimod analogue as well as a proprietary imidazole-based p38 MAPK Inhibitor. Results: All analysed p38 MAPK inhibitors resulted in significant inhibition of LPS-induced TNF-α release but with high interspecies differences for dose sensitivity. IC₅₀ values from human whole blood and PBMC showed significant higher sensitivity towards p38 MAPK inhibition compared with data from pig and rat. Conclusion: Inhibition of TNF-α release by p38 MAPK inhibitors can be reliably identified in well-established laboratory species such as rat or mouse. However, our data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans. Thus, human tissues should be considered early in the drug development process of p38 MAPK inhibitors.

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

“…In Mϕs, IL‐33 stimulates activation of p38 MAPK 21,22 . To determine if IL‐33 activates p38 MAPK in human NK cells, we measured phosphorylation of p38 MAPK and downstream targets of this kinase by flow cytometry.…”

“…To determine the role of p38 MAPK in IL‐33 enhancement of IL‐12‐induced cytokines, a specific p38 MAPK inhibitor, R‐1503, 21 was employed. NK cells were pretreated with R‐1503 (0–500 nM) for 150 min prior to stimulation with IL‐33 (10 ng/ml) and IL‐12 (1 ng/ml) for 16 h. None of the concentrations of inhibitors used in this study measurably affected cell viability (data not shown).…”

Polymyxin B Attenuates LPS-Induced Death but Aggravates Radiation-Induced Death via TLR4-Myd88-IL-6 Pathway

“…TNF-α and IL-6 were the main cytokines induced by LPS [24, 25]. And IL-10 was typical anti-inflammatory interleukins.…”

“…IL-6 and G-CSF are known radiation protection factors. TNF-α is the main factor released in endotoxemia [25, 36]. And IL-10 was typical anti-inflammatory interleukins.…”

Myricetin inhibits panel of kinases implicated in tumorigenesis

“…As the inhibitory potential of compounds on TNF‐α release in human beings is considered important early in the drug development process, and based on the significant inhibitory activity of myricetin on TNF‐α release and previous results on p38 MAPK inhibition, we decided to characterize its potential further. Tumour‐related protein kinases have become relevant molecular targets since mutation or abnormal expression of these proteins is associated with tumorigenesis and metastasis .…”