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PMID: 6590569 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Mechanisms of fever induced by recombinant human interferon.

The Journal of clinical investigation ·Vol. 74 ·No. 3 ·1984-09-00 ·Pages 906-13

Dinarello CA, Bernheim HA, Duff GW, Le HV, Nagabhushan TL, Hamilton NC, Coceani F

Abstract

Since the early trials using human interferon (hIFN) derived from blood leukocytes or cell lines, fever has been a prominent component of IFN therapy. Human protein impurities might account for the fever to cell-derived hIFN, but recombinant hIFN, free of extraneous human proteins, has produced fever in nearly all recipients during clinical trials. Our present studies were carried out to determine the mechanisms of fever due to recombinant hIFN currently being used in humans. Because recombinant hIFN is produced in Escherichia coli, in these experiments we considered contaminating endotoxin as the cause of fever. Polymyxin B, which blocks endotoxin, had no effect on the pyrogenicity of hIFN in rabbits. In addition, hIFN injected into an endotoxin-resistant strain of mice produced fever. The pyrogenicity of hIFN does not appear to involve production of leukocytic pyrogen (LP), since no circulating LP was detected in rabbits during IFN fever. Furthermore, human mononuclear cells incubated with hIFN in vitro at 10(4)-10(6) U/ml did not release LP. However, hIFN stimulated prostaglandin E2 (PGE2) release from rabbit hypothalamic tissue in vitro. Intracerebroventricular injection of hIFN into the awake cat also produced fever and a rise in PGE2 levels in the cerebrospinal fluid; both effects were reversed by treatment with indomethacin. We conclude that the fever of recombinant hIFN is not due to endotoxin but that hIFN is intrinsically pyrogenic by inducing PGE2 in the hypothalamus.

MeSH Terms
Animals Body Temperature/drug effects Cats Cerebral Ventricles/drug effects,physiology Dinoprostone Female Fever/chemically induced,physiopathology Humans Hypothalamus/drug effects,physiopathology Injections, Intraventricular Interferon Type I/administration & dosage,toxicity Male Mice Mice, Inbred C3H Prostaglandins E/cerebrospinal fluid Rabbits
Chemicals
Interferon Type I Prostaglandins E Dinoprostone
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Dinarello C A
Bernheim H A
Duff G W
Le H V
Nagabhushan T L
Hamilton N C
Coceani F
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI111508
Published
1984-09-00
Pages
906-13
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC425246
Subset
IM
Grants
NIAID NIH HHS · AI-01564 · United States
NIAID NIH HHS · AI-15614 · United States
NIAID NIH HHS · AI-17279 · United States
External Links
PubMed source DOI: 10.1172/JCI111508 PMC Full Text View journal details
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