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This version published online on August 25, 2005
Endocrinology, doi:10.1210/en.2005-0567
A more recent version of this article appeared on December 1, 2005
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Submitted on May 11, 2005
Accepted on August 17, 2005

SERTOLI CELL EXPRESSION OF STARD1 AND D5 START DOMAIN CONTAINING PROTEINS AND SREBP-1 ARE IL-1{beta} REGULATED BY ACTIVATION OF cJUN N-TERMINAL KINASE AND CYCLOOXYGENASE-2 AND CYTOKINE INDUCTION

Tomomoto Ishikawa, Keumsil Hwang, Deborah Lazzarino, and Patricia L. Morris*

Center for Biomedical Research, Population Council and The Rockefeller University, New York, NY 10021

* To whom correspondence should be addressed. E-mail: p-morris{at}popcbr.rockefeller.edu.

In testicular Sertoli cells (SC), IL-1{beta} regulates steroid, lactate and transferrin secretion; while each influences germ cell development and spermatogenesis, little is known about the signaling mechanisms involved. In other cell types, IL-1{beta} potently induces reactive oxygen species (ROS) and/or cyclooxygenase-2 (COX-2). In contrast, in Sertoli cells IL-1{beta} does not generate ROS but rapidly phosphorylates cJun-NH2-terminal kinase (JNK) but not p44/42 or p38 mitogen-activated protein kinases. Phosphorylated JNK stimulates COX-2 activity, mediating expression of interleukins and steroidogenic acute regulatory (StAR)-related (START domain containing) proteins D1 and D5, but not D4. In a time- and dose-dependent manner, IL-1{beta} rapidly increases levels of COX-2 mRNA (2-fold); induction of COX-2 protein (50-fold) requires de novo protein synthesis. Concomitantly, increases in IL-1{alpha}, IL-6, and IL-1{beta} mRNAs (1-3 h) are observed. As StARD1 mRNA decreases, StARD5 mRNA increases; substantial recovery-phase induction of StARD1 mRNA above control is noted (24 h). Inhibition of JNK or COX-2 activities prevents IL-1{beta} induction of interleukin and StARD5 mRNAs and subsequent increases in StARD1 mRNA (24 h), indicating that these effects depend on activation of both enzymes. StARD1 and D5 protein levels are significantly altered, consistent with posttranscriptional and posttranslational regulation. IL-1{beta} rapidly decreases levels of precursor and mature sterol regulatory element-binding protein-1 (SREBP-1), changes not altered by cyclohexamide, suggesting coordinate regulation of StARD1 and D5 but not D4 expression. These data demonstrate that JNK and COX-2 activities regulate Sertoli cytokines and particular START domain containing proteins, suggesting protective stress responses including transcription, protein and lipid regulation within this specialized epithelium.
Key words: START domain • steroidogenic acute regulatory protein • IL-1{alpha} • IL-6 • reactive oxygen species • JNK • COX • spermatogenesis • cholesterol • lipid • StARD4 • StARD5




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