title: Tumor necrosis factor and interleukin-1 are potent inhibitors of angiotensin-II-induced aldosterone synthesis.
abstract: Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), mediate many inflammatory and cellular responses. However, the effects of TNF and IL-1 on basal and angiotensin-II (AII)-stimulated aldosterone synthesis are not known. We studied the effect of recombinant and purified TNF and IL-1 on basal as well as AII-, ACTH-, and K+-induced aldosterone synthesis in isolated rat adrenal glomerulosa cells. Since we have previously shown that AII action is mediated by activation of the 12-lipoxygenase (12LO) pathway of arachidonic acid, we also evaluated the effects of these cytokines on the 12LO product 12-hydroxyeicosatetraenoic acid (12HETE) using a validated RIA technique. TNF at 2.5 and 5.0 ng/ml produced a dose-dependent inhibition of AII-induced aldosterone synthesis [AII, 39.0 +/- 3.3 ng/10(6) cells.h; AII plus TNF (5.0 ng/ml), 14.3 +/- 1.6; P less than 0.001 vs. AII; AII plus TNF (2.5 ng/ml), 24.7 +/- 3.2; P less than 0.01 vs. AII]. Similarly, TNF at 5.0 ng/ml also attenuated the stimulatory effect of ACTH (10(-9) M). However, K+-induced aldosterone synthesis was not altered. TNF also did not alter basal aldosterone levels. AII, as previously shown, stimulates 12HETE synthesis (basal, 608 +/- 114 pg/10(5) cells.h; versus AII, 1268 +/- 197; P less than 0.02). TNF at concentrations of 1.0-5.0 ng/ml produced a dose-dependent inhibition of AII stimulatory action on 12HETE synthesis [AII plus TNF (1.0 ng/ml), 650 +/- 26 pg, P less than 0.03 vs. AII; AII plus TNF (5.0 ng/ml), 390 +/- 46; P less than 0.01 vs. AII plus TNF (1.0 ng/ml)]. In addition, 12HETE at 10(-8) M completely restored the effects of AII during blockage by TNF. Purified human IL-1 (75% beta, 25% alpha) as well as recombinant human IL-1 beta at concentrations as low as 50 pg/ml inhibited AII-induced aldosterone synthesis. IL-1 beta did not alter ACTH- or K+-induced aldosterone synthesis and, in fact, had a tendency to potentiate ACTH effects. These results suggest that the cytokines TNF and IL-1 are potent inhibitors, particularly of AII action in the adrenal glomerulosa cell. Therefore, local or systemically produced TNF or IL-1 may be important negative modulators of aldosterone synthesis.
authors.affiliation: Section of Endocrinology, University of Southern California, Los Angeles County Medical Center 90033.
authors.forename: R
authors.initials: R
authors.lastname: Natarajan
authors.forename: S
authors.initials: S
authors.lastname: Ploszaj
authors.forename: R
authors.initials: R
authors.lastname: Horton
authors.forename: J
authors.initials: J
authors.lastname: Nadler
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000450:Aldosterone / Q000096:biosynthesis* / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015384:Zona Glomerulosa / Q000187:drug effects / Q000378:metabolism*
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D000450:Aldosterone; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000324:Adrenocorticotropic Hormone; D011188:Potassium