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Interleukin-1-Induced Chemokines in Mouse Granulosa Cells: Impact on Keratinocyte Chemoattractant Chemokine, a CXC Subfamily

Center for Reproductive Sciences (D.S.S., K.F.R), Departments of Molecular and Integrative Physiology (D.S.S.), Anatomy and Cell Biology (K.F.R), University of Kansas Medical Center, Kansas City, Kansas 66160

Address all correspondence and requests for reprints to: Deok-Soo Son, Center of Reproductive Sciences, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160-7417. E-mail: dson{at}kumc.edu.

IL-1 is well known to be involved in the immune system and have a role in ovarian inflammation as well as exhibiting inhibitory effects on steroidogenesis and folliculogenesis. Because multiple aspects of ovarian function have also been shown to involve cytokine/chemokine networks, IL-1-induced chemokine gene expression in mouse granulosa cells was investigated. Granulosa cells from immature mice at 28 d of age were cultured with IL-1 (10 ng/ml). IL-1 induced abundantly and specifically keratinocyte chemoattractant (KC) chemokine, a CXC subfamily. KC chemokine mRNA and protein were increased 1–2 h after IL-1 and then gradually decreased. The KC promoter (–701/+30) containing three nuclear factor (NF)-B sites was fully responsive to IL-1, whereas deletions and mutants of the NF-B sites lowered the responsiveness to IL-1. The proximal NF-B site (–69/–59) played a critical role in regulating IL-1-induced KC chemokine promoter activity. Overexpression of the inhibitor of NF-B (IB) blocked KC promoter activity induced by IL-1, whereas overexpression of p65, a component of NF-B, increased promoter activity and mRNA of KC chemokine. In addition, FSH did not affect NF-B signaling or IL-1-induced KC chemokine promoter activity. Within 1–3 h after ip injection of lipopolysaccharide (100 µg/mouse), a product known to stimulate release of IL-1, KC chemokine was localized in the ovary to granulosa cells as well as the thecal-interstitial layer. The results of this study indicate that KC gene is a chemokine induced acutely by IL-1 via NF-B signaling in mouse granulosa cells.