Effects of cytokine application on glucocorticoid secretion in an animal model for systemic scleroderma.
We previously reported on an altered immune-endocrine feedback loop via the hypothalamo-pituitary-adrenal (HPA) axis in Obese strain (OS) chickens afflicted with spontaneous autoimmune thyroiditis. These animals are deficient in plasma corticosterone increase after antigenic challenge or application of cytokine-containing conditioned medium of mitogen-stimulated spleen cells (CM). To investigate whether the impaired ability to respond to cytokines with glucocorticoid-increasing factor (GIF) activity, e.g. interleukin 1 (IL 1), is restricted to OS chickens as a model for an organ-specific autoimmune disease, we extended our experiments to another autoimmune-prone animal strain, the chickens of the University of California at Davis line 200 (UCD-200). These animals develop an inherited inflammatory fibrotic disease that closely resembles human progressive systemic sclerosis (scleroderma). Application of GIF-containing CM to UCD-200 chickens leads to a transient increase in glucocorticoid serum levels within 1-2 hours comparable to that of controls. But, while corticosterone levels in the latter returned to normal baseline levels after 4 hours, they were still elevated in autoimmune chickens. Although the peak of the glucocorticoid hormone serum concentrations was equal to that of controls, UCD-200 had to secrete twice as much adrenocorticotropic hormone to achieve this corticosterone serum level due to an apparent hyporesponsiveness of the adrenal gland to this secretagogue. The altered cytokine-induced glucocorticoid secretion is found in early as well as in chronic, sclerotic stages of the disease. Cellular alterations in the peripheral blood of UCD-200 chickens during the prolonged elevated corticosterone section, i.e. between 2-4 hours after CM application, are characterized by a significant decrease in the percentage of CD4+ and CD8+ cells. Furthermore, a significant increase in B cells up to 24 hours with a maximum after 1 hour was found. The proliferative response to the mitogen concanavalin A of peripheral mononuclear cells was inversely correlated to the serum corticosterone level, showing a permanent decrease of 80-90% after 1-4 hours in autoimmune animals. This functional alteration in UCD-200 was accompanied by an 80% decrease in serum interleukin 2 (sIL 2) activity 4 hours after CM application. Twenty-four hours later an eight-fold increase in sIL 2 rebound activity was found, indicating that the inhibitory effect of corticosterone in UCD-200 chickens is not long-lasting.
Brezinschek
H P
HP
Institute for General and Experimental Pathology, University of Innsbruck, Medical School, Austria.
Gruschwitz
M
M
Sgonc
R
R
Moormann
S
S
Herold
M
M
Gershwin
M E
ME
Wick
G
G
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D001685:Biological Factors / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002645:Chickens / Q000235:genetics / Q000276:immunology*; D003208:Concanavalin A / Q000494:pharmacology; D003240:Connective Tissue Diseases / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D003345:Corticosterone / Q000172:deficiency / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D005246:Feedback; D005355:Fibrosis; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000096:biosynthesis; D007958:Leukocyte Count; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D012595:Scleroderma, Systemic; D013154:Spleen / Q000166:cytology
D001685:Biological Factors; D017077:Culture Media, Conditioned; D007155:Immunologic Factors; D007376:Interleukin-2; D003208:Concanavalin A; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone