John J. Haddad^{1, 2,}, Lama H. Hanbali¹

The immunomodulatory activity of thymulin and related analogues in vivo is not well characterized in the CNS. We have previously provided evidence for an anti-inflammatory potential of thymulin in downregulating proinflammatory cytokines in a NF-κB-dependent mechanism in vitro. Furthermore, we have shown that intracerebroventricular (ICV) treatment with thymulin in the hippocampus (HC) reduced the nuclear localization and activation of NF-κB, an effect mediated by the IκB-α/pIκB- α pathway in vivo. ICV stereotaxic injection of endotoxin (ET) differentially upregulated the nuclear translocation /expression of NF-κB₁ (p50), NF-κB₂ (p52), RelA (p65), RelB (p68) and c-Rel (p75) in the HC. Pretreatment with thymulin followed by ET exposure reduced the nuclear translocation of NF-κB subunits. The anti-inflammatory effect of thymulin seems to be mediated via the IκB-α pathway since thymulin downregulated ET-induced phosphorylation of IκB-α. Stereotaxic pretreatment with synthetic peptide analogue of thymulin (PAT) reduced the nuclear translocation of NF-κB subunits, an effect mediated by downregulating the phosphorylation of IκB-α. EMSA revealed dose-dependent inhibition of NF-κB/DNA activation mediated by ICV ET. These results indicate that the anti-inflammatory effect of thymulin/PAT, mediated by IκB-α, is NF-κB-dependent and involves the downregulation of the nuclear translocation of various NF-κB subunits and their subcellular activation.

anti-inflammatory, intracerebroventricular, IκB, NF-κB, PAT, thymulin