Interleukin-2 given to asymptomatic HIV-infected individuals leads to an exaggerated response of the pituitary gland to the action of CRH.
OBJECTIVE
Studies investigating the impact of interleukin-2 (IL-2) on the corticotroph axis have shown that IL-2 can stimulate cortisol and ACTH secretion. However, the site, the time course and the mechanisms of IL-2 stimulation of the corticotroph axis are still not known. The aim of this study was to gain insight into the mechanisms of IL-2 stimulation of the corticotroph axis.


METHODS
A total of 9 x 10(6) IU/day IL-2 were given to 18 male HIV-infected patients treated with a combination of HIV antiviral drugs (usually two reverse-transcriptase inhibitors and one protease-inhibitor) over a course of 4-5 days. Seven of these 18 patients received a second course of IL-2.


RESULTS
Cortisol levels increased significantly (P < 0.001) from baseline levels (427 +/- 118 nmol/l) to 746 +/- 132 nmol/l after 4 days of IL-2 therapy with a gradual decrease to baseline within 10 days after the end of therapy. ACTH showed a similar pattern rising from 5.9 +/- 1.9 pmol/l at baseline to 12.4 +/- 4.6 pmol/l on day 4 (P < 0.001). The cortisol response after CRH application (carried out at 15.00 h) was significantly more pronounced at the end of IL-2 application (CRH test B, baseline: 330 +/- 59 nmol/l, peak 774 +/- 134 nmol/l, 135% increase) when compared to pretreatment (CRH test A, baseline: 226 +/- 73 nmol/l, peak 459 +/- 103 nmol/l, 103% increase, P </= 0.0001). The cortisol response 9 days after the end of IL-2 administration showed a similar pattern when compared to pretreatment values. The ACTH response after CRH was essentially paralleled by the cortisol response (CRH test B, baseline: 6.1 +/- 2.8 pmol/l, peak 16.0 +/- 4.4 pmol/l, 170% increase; CRH test A, baseline: 4.3 +/- 1.9 pmol/l, peak 9.2 +/- 3.1 pmol/l, 110% increase, P = 0.0005). Furthermore, we observed higher ACTH and cortisol concentrations in the morning when compared to late afternoon values during treatment with IL-2 [cortisol: baseline: 426 +/- 73 nmol/l (8.00 h); 226 +/- 73 nmol/l (15.00 h)]; day 4: [746 +/- 132 nmol/l (8.00 h); 339 +/- 59 nmol/l (15.00 h)]; ACTH: baseline: [5.9 +/- 1.9 pmol/l (8.00 h); 4.3 +/- 1.9 pmol/l (15.00 h)]; day 4: [12.4 +/- 4.7 pmol/l (8.00 h); 6.1 +/- 2.8 pmol/l (15.00 h)].


CONCLUSIONS
The data from this in vivo study suggest that IL-2 most likely resulted in corticotroph hyperplasia leading to an exaggerated response of the pituitary gland to the action of CRH.
Witzke
Oliver
O
Department of Medicine, Clinic of Endocrinology, University Clinic Essen, Germany.
Winterhagen
Toni
T
Kribben
Andreas
A
Philipp
Thomas
T
Mann
Klaus
K
Reinhardt
Walter
W
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000328:Adult; D000704:Analysis of Variance; D019380:Anti-HIV Agents / Q000627:therapeutic use; D003346:Corticotropin-Releasing Hormone; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism*; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D011446:Prospective Studies; D013268:Stimulation, Chemical
D019380:Anti-HIV Agents; D007376:Interleukin-2; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone