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J. Biol. Chem., Vol. 279, Issue 4, 2728-2736, January 23, 2004

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Transcriptional Regulation of Insulin-like Growth Factor-I by Interferon- Requires STAT-5b^*

Vivian Hwa, Brian Little, Eric M. Kofoed, and Ron G. Rosenfeld¶||

From the Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon 97239-3098, the ^¶Lucile Packard Foundation for Children's Health, Palo Alto, California 94304, and ^||Stanford University, Stanford, California 94305-2038

Insulin-like growth factor (IGF)-I, a growth factor important for cell proliferation, cellular differentiation, and multiple metabolic functions, is regulated in vivo by growth factors and cytokines, but the mechanism(s) of regulation at the cellular level is not well understood. We now demonstrate, employing primary human dermal fibroblasts (CF), that the multipotent cytokine, interferon- (IFN-), can up-regulate IGF-I mRNA expression and that this regulation occurs via activation of the signal transducer and activator of transcription-5b (STAT-5b) pathway. IFN- (100 units/ml) treatment of CF cells resulted in a preferential, time-dependent activation of STAT-5b, although both STAT-5a and STAT-5b isoforms are present. The activated STAT-5b translocated to the nucleus within 30 min of treatment and induced an increase in IGF-I mRNA of 6 ± 1.0-fold, 3 h post-treatment, with a further increase to 8 ± 1.7-fold at 5 h. In contrast, IFN- treatment of primary human dermal fibroblasts with a nonfunctional STAT-5b (PF cells) resulted in activation of only STAT-5a and an increase of the IGF-I mRNA level of 1.7 ± 0.6-fold, 5 h post-treatment. The IFN--induced regulation of the interferon regulatory factor-1 gene, whose expression is dependent on activated STAT-1, was the same between CF and PF cells. In summary, our results provide evidence of the following in human primary dermal fibroblasts: (a) IFN- preferentially activates STAT-5b, but, in the absence of a functional STAT-5b, STAT-5a is activated; (b) IFN- time-dependently up-regulates IGF-I mRNA expression; (c) the regulation of IGF-I requires an active STAT-5b, and activated STAT-5a cannot substitute for an inactive STAT-5b; and (d) STAT-5b has an essential role in the transcriptional up-regulation of IGF-I.

Received for publication, September 22, 2003 , and in revised form, October 9, 2003.

^* This work was supported by National Institutes of Health Grant CA58110 (to R. G. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pediatrics, NRC5, Oregon Health and Sciences University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098. Tel.: 503-494-1931; Fax: 503-494-0428; E-mail: hwav{at}ohsu.edu.

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