Differential Pharmacological Behaviour of P38 Inhibitors in Regulating the LPS-induced TNF-α Production in Human and Rat Whole Blood in Vitro

Overview

Journal Inflammation

Specialties Allergy & Immunology
Pathology

Date 2010 May 7

PMID 20446028

Citations 1

Authors

Merce Pont-Giralt

Nuria Godessart

Cristina Balague

Affiliations

Soon will be listed here.

Abstract

p38 inhibitors are potent TNF-α suppressors in LPS-stimulated human whole blood and promote efficacy in the rat adjuvant arthritis model. However, the anti-TNF-α activity of p38 inhibitors in rat whole blood has not been explored, preventing the establishment of a potential relation between in vitro and in vivo activity data in the same species. We have pharmacologically characterized a rat whole blood assay based on LPS stimulation. While p38 inhibitors showed good activity in the human assay, they failed to inhibit TNF-α in the rat whole blood assay. At high LPS concentration some compounds even potentiated TNF-α production in the rat assay, which could be reverted in the presence of the ERK pathway inhibitor U0126. Our results suggest that p38 contributes directly to TNF-α production in human whole blood while playing a negative regulatory role in rat blood which can be overridden by p38 inhibition in the presence of high stimulus concentration.

Citing Articles

Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation.

Jirmanova L, Giardino Torchia M, Sarma N, Mittelstadt P, Ashwell J Blood. 2011; 118(12):3280-9.

PMID: 21715315 PMC: 3179397. DOI: 10.1182/blood-2011-01-333039.

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