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RelB/p50 complexes regulate cytokine-induced YKL-40 expression

Journal of Immunology, ISSN: 1550-6606, Vol: 194, Issue: 6, Page: 2862-2870
2015
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Article Description

The secreted protein, YKL-40, has been proposed as a biomarker of a variety of human diseases characterized by ongoing inflammation, including chronic neurologic pathologies such as multiple sclerosis and Alzheimer's disease. However, inflammatory mediators and the molecular mechanism responsible for enhanced expression of YKL-40 remained elusive. Using several mouse models of inflammation, we now show that YKL-40 expression correlated with increased expression of both IL-1 and IL-6. Furthermore, IL-1 together with IL-6 or the IL-6 family cytokine, oncostatin M, synergistically upregulated YKL-40 expression in both primary human and mouse astrocytes in vitro. The robust cytokine-driven expression of YKL-40 in astrocytes required both STAT3 and NF-kB binding elements of the YKL-40 promoter. In addition, YKL-40 expression was enhanced by constitutively active STAT3 and inhibited by dominant-negative IkBa. Surprisingly, cytokine-driven expression of YKL-40 in astrocytes was independent of the p65 subunit of NF-kB and instead required subunits RelB and p50. Mechanistically, we show that IL-1- induced RelB/p50 complex formation was further promoted by oncostatin M and that these complexes directly bound to the YKL- 40 promoter. Moreover, we found that expression of RelB was strongly upregulated during inflammation in vivo and by IL-1 in astrocytes in vitro. We propose that IL-1 and the IL-6 family of cytokines regulate YKL-40 expression during sterile inflammation via both STAT3 and RelB/p50 complexes. These results suggest that IL-1 may regulate the expression of specific anti-inflammatory genes in nonlymphoid tissues via the canonical activation of the RelB/p50 complexes.

Bibliographic Details

Bhardwaj, Reetika; Yester, Jessie W; Singh, Sandeep K; Biswas, Debolina D; Surace, Michael J; Waters, Michael R; Hauser, Kurt F; Yao, Zhenqiang; Boyce, Brendan F; Kordula, Tomasz

The American Association of Immunologists

Medicine; Immunology and Microbiology

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