Interleukin-8 suppresses the toxicity and antitumor effect of interleukin-2.
The clinical application of interleukin-2 (IL-2) for the treatment of certain human malignancies has shown promise. However, the use of IL-2 in immunotherapeutic protocols has been limited due to its associated toxicities. The administration of therapeutic doses of IL-2 results in a vascular leak syndrome with associated multiple system organ edema, hypotension, and respiratory, renal, and hepatic dysfunction. Previous studies suggest that the mechanism of these toxicities involves the activation of both immune effector cells and the microvascular endothelium with resultant leukocyte-vessel wall interaction, endothelial cell injury, and subsequent invasion of normal tissues by activated leukocytes. Recently it has been demonstrated that interleukin-8 (IL-8) will inhibit leukocyte adherence to an activated endothelium. Thus, we hypothesized that IL-8 would ameliorate IL-2-evoked detrimental effects. We also investigated the influence of IL-8 on IL-2-induced antitumor efficacy. Four groups of nontumored, female, C57BL/6 mice and four groups of C57BL/6 mice with pulmonary metastases from a 3-methylcholanthrene-induced fibrosarcoma (MCA-105) were treated every 6 hr for 4 days by intraperitoneal injections of IL-2 alone, IL-2 and IL-8, IL-8 alone, or an equal volume of saline which served as our control. Upon completion of therapy, we found that IL-8 suppressed many of the IL-2-induced effects including multiple organ edema, hepatic dysfunction, leukopenia, and lymphocytic infiltration of normal organs. When the number of pulmonary metastases were counted 20 days after the cessation of therapy. IL-8 was also found to significantly ablate the IL-2-elicited antitumor efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)
Heniford
B T
BT
Department of Surgery, University of Louisville School of Medicine, Kentucky 40292.
Edwards
M J
MJ
Wilson
M A
MA
Klar
E A
EA
Doak
K W
KW
Miller
F N
FN
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004487:Edema / Q000139:chemically induced; D005260:Female; D005354:Fibrosarcoma / Q000139:chemically induced; D007376:Interleukin-2 / Q000627:therapeutic use* / Q000633:toxicity*; D016209:Interleukin-8 / Q000494:pharmacology*; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000556:secondary; D008214:Lymphocytes / Q000473:pathology; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007376:Interleukin-2; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D008748:Methylcholanthrene