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Spermatogonial Cell-Mediated Activation of an IB-Independent Nuclear Factor-B Pathway in Sertoli Cells Induces Transcription of the Lipocalin-2 Gene

Stem Cell Project Group (R.-S.F., K.Tan., T.H.), The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Bunkyo-ku, Tokyo 113-8613; Laboratory of Animal Experiment for Disease Model (M.M.), Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815; and Department of Endocrine Pharmacology (R.F., K.Tam., H.K.), Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan

Address all correspondence and requests for reprints to: Takahiko Hara, Stem Cell Project Group, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan. E-mail: thara{at}rinshoken.or.jp.

In spermatogenesis, Sertoli cells serve as supporting cells for the proliferation and differentiation of germ cells. However, it appears that Sertoli cell function is regulated by adjacent spermatogonial cells in the testis because expression of lipocalin-2 mRNA, which encodes an iron-siderophore-binding protein, is barely detectable in Sertoli cells of germ cell-deficient W/W^v mice, and more abundantly expressed in jsd/jsd mice. By employing a coculture system comprising immortalized Sertoli cells (designated as Sertoli-B) and c-Kit⁺ spermatogonial cells from 7-d-old mouse testis, we found that lipocalin-2 gene transcription in Sertoli cells is induced by a factor secreted from spermatogonial cells. Transfection of Sertoli-B cells with a series of reporter constructs encompassing an upstream region of the mouse lipocalin-2 gene revealed that a nuclear factor (NF)-B binding consensus sequence in the proximal region of lipocalin-2 gene is responsible for transcriptional activation. A major NF-B component, p65, bound to this region and translocated from the cytoplasm to the nucleus upon stimulation with spermatogonial cell-conditioned medium. Moreover, short interference RNA directed to p65 or a dominant-negative form of IB suppressed the spermatogonial cell factor-mediated transcription of lipocalin-2. However, NF-B-activating inflammatory molecules, such as IL-1ß and lipopolysaccharide, did not induce lipocalin-2 mRNA in Sertoli-B cells and the expression of lipocalin-2 was unaffected in the testis of IB-deficient mice. These results demonstrate that spermatogonial cells regulate lipocalin-2 gene expression in Sertoli cells in a manner distinct from that employed by immune cells.

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