Original Article

Deficiency of the Stress Kinase p38 Results in Embryonic Lethality: Characterization of the Kinase Dependence of Stress Responses of Enzyme-deficient Embryonic Stem Cells

Correspondence to: Christopher A. Gabel, Department of Respiratory, Allergy, Immunology, Inflammation, and Infectious Diseases, Central Research, Pfizer, Inc., Groton, CT 06340. Tel:860-441-5483 Fax:860-715-2467 E-mail:christopher_a_gabel{at}groton.pfizer.com.

Released online: 6 March 2000

The mitogen-activated protein (MAP) kinase p38 is a key component of stress response pathways and the target of cytokine-suppressing antiinflammatory drugs (CSAIDs). A genetic approach was employed to inactivate the gene encoding one p38 isoform, p38. Mice null for the p38 allele die during embryonic development. p38^1/- embryonic stem (ES) cells grown in the presence of high neomycin concentrations demonstrated conversion of the wild-type allele to a targeted allele. p38^-/- ES cells lacked p38 protein and failed to activate MAP kinase–activated protein (MAPKAP) kinase 2 in response to chemical stress inducers. In contrast, p38^1/+ ES cells and primary embryonic fibroblasts responded to stress stimuli and phosphorylated p38, and activated MAPKAP kinase 2. After in vitro differentiation, both wild-type and p38^-/- ES cells yielded cells that expressed the interleukin 1 receptor (IL-1R). p38^1/+ but not p38^-/- IL-1R–positive cells responded to IL-1 activation to produce IL-6. Comparison of chemical-induced apoptosis processes revealed no significant difference between the p38^1/+ and p38^-/- ES cells. Therefore, these studies demonstrate that p38 is a major upstream activator of MAPKAP kinase 2 and a key component of the IL-1 signaling pathway. However, p38 does not serve an indispensable role in apoptosis.

Key Words: inflammation, cytokines, mitogen-activated protein kinase, signaling, cytokine-suppressing antiinflammatory drug

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