Interleukin-2 initiates metabolic responses associated with critical illness in humans.
The cytokine interleukin-2 is a primary modulator of the immune response that occurs after infection, trauma, and transplant rejection, yet its role as a mediator of associated metabolic changes in surgical illness is unknown. We studied clinical and metabolic responses in eleven tumor-bearing humans with normal renal and hepatic function receiving bolus intravenous (I.V.) interleukin-2 (30,000 U/kg). Additional subjects (n = 6) were pretreated with the cyclooxygenase inhibitor, ibuprofen (1600 mg, orally), before interleukin-2 administration. Serial measurements were made of vital signs, symptoms, hematology, and plasma concentrations of pituitary and stress hormones and selected cytokines. Administration of interleukin-2 resulted in fever, tachyacardia, "flu-like" symptoms, and neurohormonal elaboration. The responses observed were quantitatively similar to those that occurred after endotoxin administration in healthy subjects (n = 13), but differed in the following manner: 1) the onset of fever and endocrine changes occurred after a longer latent interval (180-240 minutes vs. 60-90 minutes after endotoxin), 2) peak responses after the administration of interleukin-2 also occurred later, 3) no increased circulating tumor necrosis factor was detected after administration of interleukin-2 (peak plasma concentration was greater than 35 pg/ml vs. 270 +/- 70 pg/ml after endotoxin administration), and 4) administration of interleukin-2 but not of endotoxin was associated with increased circulating concentrations of gamma interferon (peak plasma concentration 1.7 +/- 0.2 NIH U/ml vs. less than 0.1 NIH U/ml after endotoxin administration). Fever and neurohormonal responses after interleukin-2 administration were greatly attenuated by ibuprofen administration. Interleukin-2 induces other cytokines that exert their effects largely through the cyclooxygenase pathway. Interleukin-2 may be an important signal, initiating the integrated host responses to infection and injury.
Michie
H R
HR
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115.
Eberlein
T J
TJ
Spriggs
D R
DR
Manogue
K R
KR
Cerami
A
A
Wilmore
D W
DW
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D004768:Enterotoxins / Q000494:pharmacology; D004837:Epinephrine / Q000097:blood; D004926:Escherichia coli; D005260:Female; D006728:Hormones / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced*; D009638:Norepinephrine / Q000097:blood; D010146:Pain / Q000139:chemically induced*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D004768:Enterotoxins; D006728:Hormones; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone; D007052:Ibuprofen; D009638:Norepinephrine; D004837:Epinephrine