Corticosteroid action and neuroendocrine-immune interactions.
Glucocorticoid feedback during inflammation depends on several factors, including effective corticosteroid concentrations, the temporal coordination between the immune system and the HPAA, and sensitivity of the target organ to corticosteroids. In the case of LEW/N rats, several lines of evidence indicate that CRH is aberrantly regulated, and as a consequence, the circulating corticosterone concentrations are blunted. In addition, basal ACTH and corticosterone responses differ compared to SD and F344/N rats. Therefore glucocorticoid feedback during inflammation is impaired leading to uncontrolled inflammation as observed in various models. We found that in the LEW/N rat, the regulation of the GR and MR, at least in the hippocampus, is different from F344/N rats. A similar impaired upregulation of the GR has been described in aged rats, and this has been postulated to be the cause of the altered HPAA reactivity after various stimuli in these rats. Moreover, adult LEW/N rats exhibit HPAA responses which resemble those observed during the stress hyporesponsive period of immature SD or F244/N rats. These latter data suggest that in the LEW/N rat the ontogeny and/or regulation of the HPAA is disturbed. Taken together, the impaired regulation of HPAA reactivity observed in LEW/N rats could be due to an impaired regulation of the central MR and/or GR. Although no data of GR dynamics in the context of local inflammation are available yet, this could be an additional factor determining tissue sensitivity and immune responses to corticosteroids. In humans, determination of the role of the HPAA in inflammation is more complex due to the much higher intrinsic variability between subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Derijk
R
R
Unit on Neuroendocrine Immunology and Behavior, Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892.
Sternberg
E M
EM
D000305:Adrenal Cortex Hormones / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000502:physiology; D000818:Animals; D003345:Corticosterone / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D006801:Humans; D007107:Immune System / Q000502:physiology*; D007249:Inflammation; D009490:Neurosecretory Systems / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew
D000305:Adrenal Cortex Hormones; D018377:Neurotransmitter Agents; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone