Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals.

Macrophage activation by bacterial lipopolysaccharide (LPS) promotes the secretion of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and of secondary mediators, such as teukotrienes and prostaglandins (PGs). Mice tacking the gene encoding the serine/threonine protein kinase Tp12/Cot produce low levels of TNF-α in response to LPS because of an ERK-dependent post-transcriptional defect, and they are resistant to LPS/D-galactosamine-induced endotoxin shock. In this study we demonstrate that prostaglandin E2 and its regulatory enzyme, COX-2, are also targets of Tp12-transduced LPS signals in bone marrow-derived mouse macrophages. Thus, LPS-stimulated Tp12^-/- macrophages express low levels of COX-2 and PGE2, compared with wild-type Tp12^+/+ cells. The ability of Tp12 to regulate COX-2 expression depends on ERK signals that activate p90Rsk and Msk1, which in turn phosphorylate CREB, a key regulator of COX-2 transcription. These data identify physiological targets of Tp12 signaling downstream of ERK and further implicate Tp12 in the pathophysiology of inflammation. [ABSTRACT FROM AUTHOR]