Analysis of mitogen-activated protein kinase pathways used by interleukin 1 in tissues in vivo: activation of hepatic c-Jun N-terminal kinases 1 and 2, and mitogen-activated protein kinase kinases 4 and 7

The effects of interleukin 1 (IL-1) are mediated by the activation of prote in kinase signalling pathways, which have been well characterized in cultur ed cells, We have investigated the activation of these pathways in rabbit l iver and other tissues after the systemic administration of IL-1 alpha. In liver there was 30-40-fold activation of c-Jun N-terminal kinase (JNK) and 5-fold activation of both JNK kinases, mitogen-activated protein kinase (MA PK) kinase (MKK)4 and MKK7, IL-1 alpha also caused 2-3-fold activation of p 38 MAPK; and degradation of the inhibitor of nuclear factor kappaB ('I kapp aB'). although no activation of extracellular signal-regulated protein kina se (ERK) (p42/44 MAPK) was observed, The use of antibodies against specific JNK isoforms showed that, in liver, short (p46) JNK1 and long (g54) JNK2 a re the predominant forms activated, with smaller amounts of long JNK1 and s hort JNK2, No active JNK3 was detected. A similar pattern of JNK activation was seen in lung, spleen, skeletal muscle and kidney. Significant JNK3 act ivity was detectable only in the brain, although little activation of the J NK pathway in response to IL-1 alpha was observed in this tissue. This dist ribution of active JNK isoforms probably results from a different expressio n of JNKs within the tissues, rather than from a selective activation of is oforms, We conclude that IL-1 alpha might activate a more restricted set of signalling pathways in tissues in vivo than it does in cultured cells, whe re ERK and JNK3 activation are often observed. Cultured cells might represe nt a 'repair' phenotype that undergoes a broader set of responses to the cy tokine.