A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats.
We have recently found that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is due, in part, to defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, the relative arthritis resistance of histocompatible Fischer (F344/N) rats is related to their intact responses to the same stimuli. Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1 alpha, the serotonin agonist quipazine, or synthetic rat/human corticotropin-releasing hormone (CRH). To explore the mechanism of this defect, we examined the functional integrity of the hypothalamic CRH neuron in LEW/N rats compared to F344/N rats. LEW/N rats, in contrast to F344/N rats, showed profoundly deficient paraventricular nucleus CRH mRNA levels and hypothalamic CRH content in response to SCW. Compared to F344/N rats, there was no increase in LEW/N hypothalamic CRH content or CRH release from explanted LEW/N hypothalami in organ culture in response to recombinant interleukin 1 alpha. These data provide strong evidence that the defective LEW/N corticotropin and corticosterone responses to inflammatory and other stress mediators, and the LEW/N susceptibility to experimental arthritis, are due in part to a hypothalamic defect in the synthesis and secretion of CRH. The additional finding of deficient expression in LEW/N rats of the hypothalamic enkephalin gene, which is coordinately regulated with the CRH gene in response to stress, suggests that the primary defect is not in the CRH gene but is instead related to its inappropriate regulation.
Sternberg
E M
EM
Clinical Neurosciences Branch, National Institute of Mental Health, Bethesda, MD 20892.
Young
W S
WS
Bernardini
R
R
Calogero
A E
AE
Chrousos
G P
GP
Gold
P W
PW
Wilder
R L
RL
D000818:Animals; D001168:Arthritis / Q000503:physiopathology*; D001169:Arthritis, Experimental / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D002473:Cell Wall / Q000276:immunology; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D004198:Disease Susceptibility; D004745:Enkephalins / Q000235:genetics; D005260:Female; D007031:Hypothalamus / Q000503:physiopathology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012016:Reference Values; D013045:Species Specificity; D013291:Streptococcus / Q000276:immunology; D014158:Transcription, Genetic
D004745:Enkephalins; D003346:Corticotropin-Releasing Hormone