JOURNAL ARTICLE

An atypical NF-kappa B-regulated pathway mediates phorbol ester-dependent heme oxygenase-1 gene activation in monocytes

Srivatsava Naidu, Nastiti Wijayanti, Sentot Santoso, Thomas Kietzmann, Stephan Immenschuh
Journal of Immunology 2008 September 15, 181 (6): 4113-23
18768868
Heme oxygenase (HO)-1 catalyzes the rate-limiting step of heme degradation and plays an important anti-inflammatory role via its enzymatic products carbon monoxide and biliverdin. In this study it is reported that the HO-1 gene is transcriptionally induced by the phorbol ester PMA in cell cultures of monocytic cells with a regulatory pattern that is different from that of LPS-dependent HO-1 induction in these cells. Activation of HO-1 by PMA was mediated via a newly identified kappaB element of the proximal rat HO-1 gene promoter region (-284 to -275). This HO-kappaB element was a nuclear target for the NF-kappaB subunit p65/RelA as determined by nuclear binding assays and transfection experiments with luciferase reporter gene constructs in RAW264.7 monocytes. Moreover, PMA-dependent induction of endogenous HO-1 gene expression and promoter activity was abrogated in embryonic fibroblasts from p65(-/-) mice. PMA-dependent HO-1 gene activation was reduced by an overexpressed dominant negative mutant of IkappaBalpha, but not by dominant negative IkappaB kinase-2, suggesting that the classical NF-kappaB pathway was not involved in this regulation. The antioxidant N-acetylcysteine and inhibitors of p38 MAPK or serine/threonine kinase CK2 blocked PMA-dependent HO-1 gene activation. Finally, it is demonstrated by luciferase assays with a Gal4-CHOP fusion protein that the activation of p38 MAPK by PMA was independent of CK2. Taken together, induction of HO-1 gene expression by PMA is regulated via an IkappaB kinase-independent, atypical NF-kappaB pathway that is mediated via the activation of p38 MAPK and CK2.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
18768868
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"