Fever of recombinant human interferon-alpha is mediated by opioid domain interaction with opioid receptor inducing prostaglandin E2.
We have reported that there are distinct domains in Interferon-alpha (IFNalpha) molecule mediating immune and opioid-like effects respectively. And the opioid effect of IFNalpha is mediated by mu opioid receptor. We report here the structural basis of fever induced by recombinant human IFNalpha. Two kinds of IFNalpha mutants were obtained and used to investigate the structural basis of fever of IFNalpha, which are 129Ser-IFNalpha and 38Leu-IFNalpha. The antiviral activity of 129Ser-IFNalpha almost disappeared, but there still retained the strong analgesic activity. The antiviral activity of 38Leu-IFNalpha remained, but the analgesic activity disappeared completely. It showed that IFNalpha and 129Ser-IFNalpha decreased cAMP production, induced the fever, and stimulated PGE2 to release from the hypothalamus slices, which could be blocked by naloxone, but 38Leu-IFNalpha failed. It is the first demonstration that fever induced by IFNalpha is mediated by opioid domain of IFNalpha interacting with opioid receptor. It is inferred that high-activity and low side-effect IFNalpha or other cytokines could be obtained after being changed the motifs in the tertiary structure.
Department of Nautical Medicine, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, P.R. China.
Yun-Xia
YX
Wang
Wei-Gang
WG
Xu
Xue-Jun
XJ
Sun
Yi-Zhang
YZ
Chen
Xin-Yuan
XY
Liu
Hao
H
Tang
Chun-Lei
CL
Jiang
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001831:Body Temperature / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D005334:Fever / Q000276:immunology* / Q000378:metabolism*; D007370:Interferon Type I / Q000009:adverse effects* / Q000235:genetics / Q000494:pharmacology; D008297:Male; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism* / Q000502:physiology; D011994:Recombinant Proteins; D012007:Rectum / Q000276:immunology / Q000502:physiology
D007370:Interferon Type I; D011957:Receptors, Opioid; D011994:Recombinant Proteins; D000242:Cyclic AMP; D015232:Dinoprostone