IL-6/IFN-beta-2 as a circulating hormone. Induction by cytokine administration in humans.
IL-6/IFN-beta 2 is a family of phosphoglycoproteins ranging in size from 19 to 30 kDa which elicits a broad range of physiologic and immune responses. Several cytokines, including TNF, have been shown to stimulate IL-6 production in cell culture. In this report, we describe the rapid induction of circulating biologically active IL-6 by the systemic administration of rTNF to patients with cancer. Low levels of IL-6 activity could be detected in the sera of patients as early as 5 min after rTNF infusion. IL-6 levels peaked approximately 2 to 3 h after rTNF bolus administration and were undetectable in most cases within 8 h. IL-6 was detected in two separate bioassays--the hybridoma B9 proliferation and the hepatocyte-stimulating factor assay. Maximum detectable levels of IL-6 ranged from 160 to 310 hybridoma growth factor units and 11-82 ng/ml in the hepatocyte-stimulating factor assay. IL-6 induction decreased after serial, daily doses of rTNF. Serial serum samples of patients receiving IL-2 or IFN-alpha were also assayed for IL-6 production. IL-2-treated but not IFN-alpha-treated patients generated low levels of IL-6 (range less than 20 to 95 hybridoma growth factor units/ml). Interestingly, in patients treated with IL-2, serum levels of TNF were detectable and peak TNF activity preceded measurable IL-6 levels. Serum levels of acute phase plasma proteins and of corticosteroid rose in response to rTNF administration. C-reactive protein increased (2.5 to 4.0-fold) within 8 h of rTNF administration and cortisol levels rose (10- to 20-fold) within 4 h after rTNF injection. We conclude that rTNF administration in man leads to the induction of circulating IL-6 which, due to its broad range of activities, may be an important physiologic signal regulating the immune response.
Jablons
D M
DM
Surgery Branch, National Cancer Institute, Bethesda, MD 20892.
Mulé
J J
JJ
McIntosh
J K
JK
Sehgal
P B
PB
May
L T
LT
Huang
C M
CM
Rosenberg
S A
SA
Lotze
M T
MT
D002097:C-Reactive Protein / Q000096:biosynthesis / Q000097:blood; D002846:Chromatography, Affinity; D005956:Glucose-6-Phosphate Isomerase / Q000096:biosynthesis / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis / Q000097:blood; D007275:Injections, Intravenous; D015850:Interleukin-6; D007378:Interleukins / Q000096:biosynthesis* / Q000097:blood / Q000302:isolation & purification; D008970:Molecular Weight; D009369:Neoplasms / Q000097:blood*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000097:blood
D015850:Interleukin-6; D007378:Interleukins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D005956:Glucose-6-Phosphate Isomerase; D006854:Hydrocortisone