Selective upregulation of cardiac brain natriuretic peptide at the transcriptional and translational levels by pro-inflammatory cytokines and by conditioned medium derived from mixed lymphocyte reactions via p38 MAP kinase.
An increase in circulating brain natriuretic peptide (BNP) but not atrial natriuretic factor ( ANF) is observed coincident with cardiac allograft rejection that is reversed upon treatment with anti-lymphocyte therapy suggesting that pro-inflammatory cytokines may uniquely modulate BNP gene expression and secretion. This study tested pro-inflammatory cytokines or conditioned medium (CM) derived from mixed- lymphocyte reaction (MLR) cultures in their ability to modulate ANF or BNP mRNA expression, secretion, as well as BNP promoter activity in cultured neonatal rat cardiocytes. IL-1 beta and TNF-alpha elicited a significant dose- and time-dependent increase in BNP mRNA, and secretion, whereas, ANF mRNA levels and secretion did not change. IL-1 beta and TNF-alpha rapidly increased phosphorylated p38 MAP kinase abundance and activity. Inhibition of p38 MAP kinase with SB203580 abolished IL-1 beta- and TNF-alpha- stimulated increase in BNP mRNA, promoter activity and secretion. MLR-CM in 20%, 50% and 100% proportions increased BNP but not ANF secretion. The MLR-induced increases in BNP secretion were completely abolished by SB203580 pre-treatment. These investigations show that exposure of cultured rat cardiocytes to specific pro-inflammatory cytokines as well as MLR-CM results in the only known instance of upregulation of cardiac BNP at the transcriptional and translational levels without a corresponding increase in ANF gene expression. Furthermore, these effects are dependent on signaling by p38 MAP kinase. In all, the findings reveal a unique dis-coordinated expression of BNP and ANF to inflammatory cytokines and offers an opportunity to better understand the differential regulation of these two cardiac-derived endocrine hormones that share receptors as well as biological properties.[1]References
- Selective upregulation of cardiac brain natriuretic peptide at the transcriptional and translational levels by pro-inflammatory cytokines and by conditioned medium derived from mixed lymphocyte reactions via p38 MAP kinase. Ma, K.K., Ogawa, T., de Bold, A.J. J. Mol. Cell. Cardiol. (2004) [Pubmed]
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