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

AUTOR(ES)

G.Eliopoulos, Aristides

FONTE

Oxford University Press

RESUMO

Macrophage activation by bacterial lipopolysaccharide (LPS) promotes the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and of secondary mediators, such as leukotrienes and prostaglandins (PGs). Mice lacking the gene encoding the serine/threonine protein kinase Tpl2/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 Tpl2-transduced LPS signals in bone marrow-derived mouse macrophages. Thus, LPS-stimulated Tpl2–/– macrophages express low levels of COX-2 and PGE2, compared with wild-type Tpl2+/+ cells. The ability of Tpl2 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 Tpl2 signaling downstream of ERK and further implicate Tpl2 in the pathophysiology of inflammation.

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