title: RelB/p50 complexes regulate cytokine-induced YKL-40 expression.
abstract: 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-κB binding elements of the YKL-40 promoter. In addition, YKL-40 expression was enhanced by constitutively active STAT3 and inhibited by dominant-negative IκBα. Surprisingly, cytokine-driven expression of YKL-40 in astrocytes was independent of the p65 subunit of NF-κB 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.
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
authors: Reetika
authors: R
authors: Bhardwaj
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
authors: Jessie W
authors: JW
authors: Yester
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
authors: Sandeep K
authors: SK
authors: Singh
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
authors: Debolina D
authors: DD
authors: Biswas
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
authors: Michael J
authors: MJ
authors: Surace
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
authors: Michael R
authors: MR
authors: Waters
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
authors: Kurt F
authors: KF
authors: Hauser
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642; and.
authors: Zhenqiang
authors: Z
authors: Yao
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642; and.
authors: Brendan F
authors: BF
authors: Boyce
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298. tkordula@vcu.edu.
authors: Tomasz
authors: T
authors: Kordula
mesh_terms: D054392:Adipokines / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology; D037102:Lectins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D053683:Oncostatin M / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; C509289:Chil1 protein, mouse; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines; D006023:Glycoproteins; D007375:Interleukin-1; D015850:Interleukin-6; D037102:Lectins; D046912:Multiprotein Complexes; D052002:NF-kappa B p50 Subunit; D050796:STAT3 Transcription Factor; D053683:Oncostatin M; D051841:Transcription Factor RelB