IL-1 Receptor Antagonist (IL-1ra) Augments IL-2-Induced Pulmonary Vascular Leak

• Published in: The Journal of surgical research Vol. 54; no. 4; pp. 336 - 341
• Main Authors: Thom, Arleen K., Fraker, Douglas L., Norton, Jeffrey A.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01.04.1993; Elsevier
• Subjects: Animals; Biological and medical sciences; Capillary Permeability - drug effects; Drug Synergism; Drug toxicity and drugs side effects treatment; Female; Gene Expression; Interleukin-1 - genetics; Interleukin-2 - pharmacology; Interleukin-6 - metabolism; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Pharmacology. Drug treatments; Pulmonary Circulation - drug effects; Receptors, Interleukin-1 - antagonists & inhibitors; RNA, Messenger - metabolism; Toxicity: respiratory system, ent, stomatology; Edema; Respiratory disease; Toxicity; Rodentia; Leak; Cardiovascular disease; Prevention; Vertebrata; Mammalia; Interleukin 2; Mouse; Pulmonary vessel; Animal; Interleukin 1
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.1993.1054

Interleukin-2 (IL-2) therapy is dose limited by a severe vascular leak with resulting systemic and pulmonary toxicity. Although recognized as a mediator of septic shock and vascular leak, the relative role of IL-1 in IL-2 toxicity is unclear. We evaluated the effect of IL-1 receptor antagonist (IL-1ra) on IL-2 lethality, pulmonary vascular leak, and treatment of pulmonary metastases in a murine model. In vivo induction of mRNA for IL-1α was evaluated in liver by Northern blots after 0, 5, 8, and 11 doses of IL-2 in C3H/HEN mice. The expression index for the IL-1α gene increased from 0.16 to 0.74 after 6 doses of IL-2, and further increased to 1.04 after 11 doses of IL-2. C3H/HEN mice ( n = 56) were randomized to receive phosphate-buffered saline (PBS), IL-1ra high dose (HD), or IL-1ra low dose (LD) by continuous subcutaneous infusion via Alzet minipumps. The biologic effectiveness of the dose and administration of IL-1ra was determined by the ability to block IL-1-induced IL-6 production in vivo. Mean serum IL-6 levels 3 hr after intraperitoneal IL-1α (10 μg/kg) were: PBS, 3730 ± 526 (mean ± SEM pg/ml); IL-1ra (LD), 1156 ± 398; and IL-1ra (HD), 594 ± 30 ( P < 0.01, IL-1ra HD or LD vs PBS). Pulmonary vascular leak was measured by iv I 125 albumin after 8 doses of IL-2 (100,000 U ip q 8 hr). C3H/HEN mice ( n = 8 per group) given additional IL-2 doses were followed for survival. There was an increase in vascular leak in lungs of mice treated with IL-1ra (HD) plus IL-2 compared to IL-2 plus Hank's balanced salt solution (8597 ± 808 cpm vs 6975 ± 452; P < 0.05). IL-1ra did not affect survival of mice treated with repeated doses of IL-2. The effect of IL-1ra on IL-2 therapy of 10-day pulmonary metastases was evaluated with MC 38 tumor in C57BL6 mice. IL-2 significantly reduced the number of pulmonary metastases and IL-1ra had no further effect on IL-2 response. These results suggest that endogenous IL-1 is produced during IL-2 therapy and that blockade of its effects by IL-1ra does not reduce either the toxicity or the efficacy of IL-2 therapy. Endogenous IL-1 production may be a beneficial response during IL-2 therapy in ameliorating pulmonary vascular leak.