In vitro regulation of pituitary ACTH secretion in inflammatory disease susceptible Lewis (LEW/N) and inflammatory disease resistant Fischer (F344/N) rats.
We have previously shown that susceptibility to inflammatory disease in Lewis (LEW/N) rats is related to their limited hypothalamic-pituitary-adrenal (HPA) axis responses to a variety of inflammatory stimuli, while the relative resistance to inflammatory disease in Fischer (F344/N) rats is related to their potent HPA axis responses to these same stimuli. In vivo studies also showed that LEW/N pituitary ACTH responses to exogenous corticotropin-releasing hormone (CRH) were blunted compared to F344/N. To determine if there is a fundamental difference in pituitary corticotroph function between the two strains, independent of other factors influencing the HPA axis, we compared ACTH responses to a variety of stimuli in LEW/N and F344/N primary pituitary cell cultures. Here we show that in vitro basal ACTH secretion and peak ACTH response to CRH, forskolin and 8-bromo-cAMP are 50% lower in LEW/N than F344/N rats. However, these findings can be explained by other observations: diminished basal ACTH content, POMC mRNA, and a decreased number of corticotrophs, in pituitary cell cultures from LEW/N compared to F344/N rats. In addition, LEW/N corticotrophs were more sensitive to dexamethasone and to corticosterone suppression of CRH-stimulated ACTH secretion compared to F344/N. The data support the possibility of an HPA axis defect in LEW/N rats at the pituitary level which could be secondary to prolonged understimulation by hypothalamic CRH, or could also be partially related to enhanced glucocorticoid feedback inhibition.
Zelazowski
P
P
Unit on Neuroendocrine Immunology and Behavior, NICHD, NIH, Bethesda, Md. 20892.
Smith
M A
MA
Gold
P W
PW
Chrousos
G P
GP
Wilder
R L
RL
Sternberg
E M
EM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004198:Disease Susceptibility; D005246:Feedback; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology*; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew
D005938:Glucocorticoids; D012333:RNA, Messenger; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone