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  • Title: Thymulin and zinc (Zn2+)-mediated inhibition of endotoxin-induced production of proinflammatory cytokines and NF-kappaB nuclear translocation and activation in the alveolar epithelium: unraveling the molecular immunomodulatory, anti-inflammatory effect of thymulin/Zn2+ in vitro.
    Author: Haddad JJ.
    Journal: Mol Immunol; 2009 Dec; 47(2-3):205-14. PubMed ID: 19850345.
    Abstract:
    The immunomodulatory potential of thymulin and zinc (Zn(2+)) in the perinatal alveolar epithelium is not well characterized. In an in vitro model of fetal alveolar type II epithelial cells (FATEII), we have investigated the exhibition of an anti-inflammatory activity of this peptide hormone. Thymulin selectively ameliorated, in a dose-dependent manner, the endotoxin (ET/LPS [lipopolysaccharide])-induced release of IL-1beta, but not IL-6 or TNF-alpha. Furthermore, Zn(2+), an anti-inflammatory antioxidant, which is required for the biological activity of thymulin, independently reduced the secretion of IL-1beta, TNF-alpha and, to a lesser extent, at a supraphysiologic dose (1 mM), IL-6. The underlying cellular and molecular pathways associated with the anti-inflammatory effect of thymulin and Zn(2+) in the alveolar epithelium are not well established. Further in this study, the role of cyclic AMP (cAMP) in the anti-inflammatory effect of thymulin was investigated, in addition to unraveling the possible involvement of the NF-kappaB pathway. Interestingly, thymulin upregulated, in a dose- and time-dependent manner, the release of the nucleotide cAMP. To understand whether the inhibitory effect of thymulin on cytokine release is cAMP-dependent, Forskolin, a labdane diterpene known to elevate intracellular cAMP, was shown to reduce the secretion of IL-1beta and TNF-alpha, but not IL-6, an effect mimicked by dibutyryl-cAMP (dbcAMP), an analog of cAMP. Alveolar epithelial cells treated with thymulin markedly showed a downregulation of the nuclear translocation of RelA (p65), the major transactivating member of the NF-kappaB family, in addition to NF-kappaB(1) (p50) and c-Rel (p75), an effect mildly substantiated with Zn(2+). Furthermore, thymulin/Zn(2+) reduced, in a dose-dependent manner, the DNA-binding activity of NF-kappaB (RelA/p65). These results indicate that the anti-inflammatory effect of thymulin, which is mediated by cAMP, is NF-kappaB-dependent and involves the downregulation of the release of proinflammatory cytokines, particularly IL-1beta, an effect synergistically amplified, at least in part, by Zn(2+). The molecular regulation of thymulin via a NF-kappaB-dependent pathway is critical to understanding the anti-inflammatory alleviating role of this nonapeptide in regulating proinflammatory signals.
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