TY - JOUR
T1 - Deficient tryptophan catabolism along the kynurenine pathway reveals that the epididymis is in a unique tolerogenic state
AU - Jrad-Lamine, Aicha
AU - Henry-Berger, Joelle
AU - Gourbeyre, Pascal
AU - Damon-Soubeyrand, Christelle
AU - Lenoir, Alain
AU - Combaret, Lydie
AU - Saez, Fabrice
AU - Kocer, Ayhan
AU - Tone, Shigenobu
AU - Fuchs, Dietmar
AU - Zhu, Wentao
AU - Oefner, Peter J.
AU - Munn, David H.
AU - Mellor, Andrew L.
AU - Gharbi, Najoua
AU - Cadet, Rémi
AU - Aitken, R. John
AU - Dreveta, Joël R.
PY - 2011/3/11
Y1 - 2011/3/11
N2 - Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway. Intriguingly, IDO is constitutively and highly expressed in the mammalian epididymis in contrast to most other tissues where IDO is induced by proinflammatory cytokines, such as interferons. To gain insight into the role of IDO in the physiology of the mammalian epididymis, we studied both wild type and Ido1-/--deficient mice. In the caput epididymis of. Ido1-/- animals, the lack of IDO activity was not compensated by other tryptophan-catabolizing enzymes and led to the loss of kynurenine production. The absence of IDO generated an inflammatory state in the caput epididymis as revealed by an increased accumulation of various inflammation markers. The absence of IDO also increased the tryptophan content of the caput epididymis and generated a parallel increase in caput epididymal protein content as a consequence of deficient proteasomal activity. Surprisingly, the lack of IDO expression had no noticeable impact on overall male fertility but did induce highly significant increases in both the number and the percentage of abnormal spermatozoa. These changes coincided with a significant decrease in white blood cell count in epididymal fluid compared with wild type mice. These data provide support for IDO playing a hitherto unsuspected role in sperm quality control in the epididymis involving the ubiquitination of defective spermatozoa and their subsequent removal.
AB - Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway. Intriguingly, IDO is constitutively and highly expressed in the mammalian epididymis in contrast to most other tissues where IDO is induced by proinflammatory cytokines, such as interferons. To gain insight into the role of IDO in the physiology of the mammalian epididymis, we studied both wild type and Ido1-/--deficient mice. In the caput epididymis of. Ido1-/- animals, the lack of IDO activity was not compensated by other tryptophan-catabolizing enzymes and led to the loss of kynurenine production. The absence of IDO generated an inflammatory state in the caput epididymis as revealed by an increased accumulation of various inflammation markers. The absence of IDO also increased the tryptophan content of the caput epididymis and generated a parallel increase in caput epididymal protein content as a consequence of deficient proteasomal activity. Surprisingly, the lack of IDO expression had no noticeable impact on overall male fertility but did induce highly significant increases in both the number and the percentage of abnormal spermatozoa. These changes coincided with a significant decrease in white blood cell count in epididymal fluid compared with wild type mice. These data provide support for IDO playing a hitherto unsuspected role in sperm quality control in the epididymis involving the ubiquitination of defective spermatozoa and their subsequent removal.
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U2 - 10.1074/jbc.M110.172114
DO - 10.1074/jbc.M110.172114
M3 - Article
C2 - 21189261
AN - SCOPUS:79953149140
SN - 0021-9258
VL - 286
SP - 8030
EP - 8042
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -