Analysis of the heterogeneity of the biological responses to native and mutant human interleukin-6.
The structure-function relationships of the biological activities of mutant varieties of the pleiotropic cytokine interleukin-6 (human) were measured by three assays: induction of immunoglobulin M (IgM) secretion from an Epstein-Barr virus-transformed human B cell line and induction of fibrinogen secretion from either a human hepatoma cell line or a rat hepatoma cell line. The biological effects of the cytokine were characterized by three parameters as determined by a novel analysis: effectiveness (the maximal response attainable), efficiency (the concentration yielding a half-maximal response), and complexity (a measure of heterogeneity and feedback control). Substitution of serine for cysteine was associated with a reduction in the effectiveness of interleukin-6 in both fibrinogen secretion assays. In the assay with human hepatoma cells, there was also a profound reduction in efficiency. Serine substitution in the human IgM synthesis assay appears mainly to reduce the efficiency. Deletion of amino acids 4 to 23 increased the efficiency in the rat hepatoma assay. The complexity parameter suggests the presence of multiple receptor classes or negative feedback in all three assays. Use of the proposed sequential approach to the analysis of dose-response relations in bioassays provides a more useful quantitative assessment of activities as well as more insight into the complexity of the reactions.
Krakauer
T
T
Disease Assessment Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 20702-5011.
Snouwaert
J N
JN
Fowlkes
D M
DM
Krakauer
H
H
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D002472:Cell Transformation, Viral / Q000502:physiology; D004854:Herpesvirus 4, Human; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D009154:Mutation; D051381:Rats; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D007075:Immunoglobulin M; D015850:Interleukin-6