Chen Haolin, Luo Lindi, Liu June, Zirkin Barry R
Department of Biochemistry and Molecular Biology, Division of Reproductive Biology, Johns Hopkins University Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205, USA.
Endocrinology. 2007 Feb;148(2):735-42. doi: 10.1210/en.2006-0925. Epub 2006 Oct 26.
Previous studies suggested that increased Leydig cell cyclooxygenase (COX)2 expression may be involved in the reduced testosterone production that characterizes aged Leydig cells. Our objective herein was to further elucidate the relationships among LH stimulation, Leydig cell COX2 and COX1 expression, aging, and testosterone production. Incubation of Leydig cells from young or aged rats with LH or dibutyryl cAMP resulted in increases in both intracellular COX2 protein expression and testosterone production. COX1 expression did not respond to LH or dibutyryl cAMP. Incubation of adult cells with a protein kinase A inhibitor suppressed the stimulatory effects of LH on COX2 and testosterone production. Short-term incubation of Leydig cells with TGF-alpha or IL-1beta also increased COX2 protein levels; IGF-I had no effect. In vivo, LH also was found to stimulate both COX2 and testosterone, but not COX1. As reported previously, COX2 expression was greater in old than in young cells, and old Leydig cells responded to inhibition of COX2 in vitro with increased testosterone production. However, the effects of the COX2 inhibitors were not restricted to old cells; young Leydig cells also responded to COX2 inhibition with increased testosterone production. This and the observation that the incubation of young or old cells with LH resulted in increased COX2 and testosterone production in both cases suggests that the relationship between COX2 and testosterone production is not unique to aged Leydig cells. Moreover, the close correlation between increases in COX2 and testosterone in LH-stimulated young and aged Leydig cells is difficult to reconcile with the contention that the increased expression of COX2 in aged cells is responsible for age-related suppression of Leydig cell testosterone production.
先前的研究表明，睾丸间质细胞中环氧化酶（COX）2表达增加可能与老年睾丸间质细胞中睾酮生成减少有关。我们在此的目的是进一步阐明促黄体生成素（LH）刺激、睾丸间质细胞COX2和COX1表达、衰老与睾酮生成之间的关系。用LH或二丁酰环磷腺苷（dibutyryl cAMP）孵育年轻或老年大鼠的睾丸间质细胞，导致细胞内COX2蛋白表达和睾酮生成均增加。COX1表达对LH或二丁酰环磷腺苷无反应。用蛋白激酶A抑制剂孵育成年细胞可抑制LH对COX2和睾酮生成的刺激作用。用转化生长因子-α（TGF-α）或白细胞介素-1β（IL-1β）短期孵育睾丸间质细胞也可增加COX2蛋白水平；胰岛素样生长因子-I（IGF-I）无作用。在体内，也发现LH可刺激COX2和睾酮，但不刺激COX1。如先前报道，老年细胞中的COX2表达高于年轻细胞，并且老年睾丸间质细胞在体外对COX2抑制的反应是睾酮生成增加。然而，COX2抑制剂的作用并不局限于老年细胞；年轻睾丸间质细胞对COX2抑制的反应也是睾酮生成增加。这一点以及用LH孵育年轻或老年细胞均导致COX2和睾酮生成增加的观察结果表明，COX2与睾酮生成之间的关系并非老年睾丸间质细胞所特有。此外，在LH刺激的年轻和老年睾丸间质细胞中，COX2增加与睾酮增加之间密切相关，这难以与老年细胞中COX2表达增加导致睾丸间质细胞睾酮生成的年龄相关性抑制这一观点相协调。
