Role of NF-kB and p38 MAP Kinase Signaling Pathways in the Lipopolysaccharide-Dependent Activation of Heme Oxygenase-1 Gene Expression

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Abstract
Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation, which is up-regulated by a host of stress stimuli. The bacterial cell membrane component lipopolysaccharide (LPS) is a prototypical activator of monocytic cells. Here, it is shown that LPS induced the endogenous HO-1 gene expression in RAW264.7 monocytic cells. To investigate the molecular mechanisms of HO-1 gene induction by LPS, we performed transfection experiments with reporter gene constructs containing sequences of the proximal rat HO-1 gene promoter. Deletion and mutation analysis indicated that a cyclic AMP response element/activator protein-1 site (–664/–657), but not an E-box motif (–47/–42), played a major role for LPS-dependent HO-1 gene induction. Up-regulation of HO-1 promoter activity by LPS was decreased by pharmacological nuclear factor-kB (NF-kB) inhibitors and by cotransfected expression vectors with dominant negative isoforms of NF-kB-inducing kinase, inhibitor of NF-kB (IkB) kinase β, and IkBα. Moreover, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and overexpressed dominant negative p38β decreased, whereas dominant negative p38δ increased, LPS-dependent induction of HO-1 gene expression. The results suggest that the NF-kB and p38 MAPK signaling pathways mediate the LPS-dependent induction of HO-1 gene expression via DNA sequences of the proximal promoter region. Antioxid. Redox Signal. 6, 802–810.

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