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Original Article

Deficiency of the Stress Kinase P38 Results in Embryonic Lethality

Melanie Allen^b, Linne Svensson^a, Marsha Roach^b, John Hambor^b, John McNeish^b, and Christopher A. Gabel^a

^a Department of Respiratory, Allergy, Immunology, Inflammation, and Infectious Diseases
^b Department of Genetic Technologies, Pfizer Central Research, Groton, Connecticut 06340
Department of Respiratory, Allergy, Immunology, Inflammation, and Infectious Diseases, Central Research, Pfizer, Inc., Groton, CT 06340.860-715-2467860-441-5483

christopher_a_gabel{at}groton.pfizer.com

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

© 2000 The Rockefeller University Press

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