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Thyroid hormone analogues potentiate the antiviral action of interferon‐γ by two mechanisms
Author(s) -
Lin H.Y.,
Thacore H.R.,
Davis F.B.,
Davis P.J.
Publication year - 1996
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199605)167:2<269::aid-jcp10>3.0.co;2-3
Subject(s) - cycloheximide , triiodothyronine , endocrinology , medicine , interferon , hormone , incubation , long term potentiation , in vitro , biology , cell culture , virology , biochemistry , genetics , receptor
L‐thyroxine (L‐T 4 ) potentiates the antiviral activity of human interferon‐γ (IFN‐γ) in HeLa cells. We have added thyroid hormone and analogues to cells either 1) for 24 h pretreatment prior to 24 h of IFN‐γ (1.0 IU/ml), 2) for 24 h cotreatment with IFN‐γ, 3) for 4 h, after 20 h cell incubation with IFN‐γ, alone, or 4) for 24 h pretreatment and 24 h cotreatment with IFN‐γ. The antiviral effect of IFN‐γ was then assayed. L‐T 4 potentiated the antiviral action of IFN‐γ by a reduction in virus yield of more than two logs, the equivalent of a more than 100‐fold potentiation of the IFN's antiviral effect. 3,3′,5‐L‐triiodothyronine (L‐T 3 ) was as effective as L‐T 4 when coincubated for 24 h with IFN‐γ but was less effective than L‐T 4 when coincubated for only 4 h. D‐T 4 , D‐T 3 , 3,3′,5‐triiodothyroacetic acid (triac), tetraiodothyroacetic acid (tetrac), and 3,5‐diiodothyronine (T 2 ) were inactive. When preincubated with L‐T 4 for 24 h prior to IFN‐γ treatment, tetrac blocked L‐T 4 potentiation, but, when coincubated with L‐T 4 for 4 h after 20 h IFN‐γ, tetrac did not inhibit the L‐T 4 effect. 3,3′,5′‐L‐triiodothyronine (rT 3 ) also potentiated the antiviral action of IFN‐γ, but only in the preincubation model. Furthermore, the effects of rT 3 preincubation and L‐T 3 coincubation were additive, resulting in 100‐fold potentiation of the IFN‐γ effect. When L‐T 4 , L‐T 3 , or rT 3 , plus cycloheximide (5 μg/ml), was added to cells for 24 h and then removed prior to 24 h IFN‐γ exposure, the potentiating effect of the three iodothyronines was completely inhibited. In contrast, IFN‐γ potentiation by 4 h of L‐T 4 or L‐T 3 coincubation was not inhibited by cycloheximide (25 μg/ml). These studies demonstrate two mechanisms by which thyroid hormone can potentiate IFN‐γ's effect: 1) a protein synthesis‐dependent mechanism evidenced by enhancement of IFN‐γ's antiviral action by L‐T 4 , L‐T 3 , or rT 3 preincubation, and inhibition of enhancement by tetrac and cycloheximide, and 2) a protein synthesis‐independent (posttranslational) mechanism, not inhibited by tetrac or cycloheximide, demonstrated by 4 h coincubation of L‐T 4 or L‐T 3 , but not rT 3 , with IFN‐γ. The protein synthesis‐dependent pathway is responsive to rT 3 , a thyroid hormone analogue generally thought to have little effect on protein synthesis. A posttranslational mechanism by which the antiviral action of IFN‐γ can be regulated has not previously been described. © 1996 Wiley‐Liss, Inc.