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Neuroimmunomodulation. 2009 Nov 17;17(2):88-96
Authors: Takayasu S, Iwasaki Y, Nigawara T, Asai M, Yoshida M, Kageyama K, Suda T
Objective: The precise mechanism whereby proinflammatory cytokines activate the hypothalamo-pituitary-adrenal axis is still unclear.
We examined whether transcription factors nuclear factor (NF)-kappaB and Nurr-1 are involved in the cytokine-induced proopiomelanocortin (POMC) gene expression.
Methods: The mouse corticotropinoma cell line AtT20 was treated with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta).
Real-time PCR, luciferase assay and Western blotting were conducted to assess the gene expression, promoter activity and protein expression in various conditions.
Results: Intrinsic expression of NF-kappaB was confirmed by RT-PCR.
An active component of NF-kappaB (p65) was upregulated in the nuclear fraction by both TNF-alpha and IL-1beta treatment in a dose- and time-related manner.
These cytokines potently stimulated the promoter activity of NF-kappaB and Nurr-1.
We also found rapid upregulation of the Nurr-1 gene and protein after treatment with these cytokines.
Cotreatment of the cells with either of the cytokines and corticotropin-releasing hormone resulted in additive effects.
Cytokine-induced Nurr-1 transcription and Nurr-1 transcription induced by overexpression of NF-kappaB were both blunted by mutagenesis within the NF-kappaB responsive element, which implies that Nurr-1 upregulation specifically requires NF-kappaB binding to its own DNA-binding site.
Proinflammatory cytokines exert positive effects on POMC gene expression, which were inhibited by pretreatment with a specific NF-kappaB inhibitor.
Conclusion: These results together imply that Nurr-1 expression is a connecting point between neuroendocrine and immune systems in mediating cytokine-induced POMC gene expression.
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Interpretation:
Pro-inflammatory cytokines bind to cytokine receptors on corticotroph cells of the anterior pituitary This then stimulates the production of Nuclear Factor Kappa Beta (NF-kappaB), an intracellular signal-transduction protein.
NF-kappaB then binds to its DNA-binding site. This then induces the production of Nurr-1 via upregulation of the Nurr-1 gene.
Nurr-1 then induces the production of Proopiomelanocortin (POMC), the precursor for ACTH, Melanocyte stimulating hormone, beta-Lipotropin, and beta-Endorphin.
Cotreatment with both pro-inflammatory cytokines and CRC (corticotropin-releasing hormone) have an additive effect on POMC production.