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J. Biol. Chem., Vol. 280, Issue 52, 42766-42773, December 30, 2005

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Adenovirus-mediated Gene Transfer of Mutated IB Kinase and IB Reveal NF-B-dependent as Well as NF-B-independent Pathways of HAS1 Activation^*

From the Ludwig Boltzmann Institute for Rheumatology and Balneology, 1100 Vienna, Austria

It has become increasingly clear that hyaluronan is more than the simple matrix molecule it was once thought to be but instead takes part in a multitude of biological functions. Three genes encode for hyaluronan synthases (HAS). We demonstrated earlier that HAS2 and HAS3 are constitutively activated in type-B synoviocytes (fibroblast-like synoviocytes) and, furthermore, that the only gene that readily responds to stimulation with a series of proinflammatory cytokines is HAS1. Here we probe the involvement of the transcription factor NF-B in induced and noninduced HAS activation. Transforming growth factor (TGF) 1 as well as interleukin (IL)-1 are both strong inducers of HAS1 transcription. Stimulation of fibroblast-like synoviocytes with IL-1 resulted in rapid degradation of IB, an event that was preceded by IB phosphorylation. Interestingly, TGF1 neither affected IB levels, nor did it cause phosphorylation of IB. In addition, TGF1 had no effect on IB and IB levels. Electrophorectic mobility shift assays demonstrate that IL-1 is a potent inducer of NF-B translocation; however, TGF1 treatment did not result in shifting bands. Two adenovirus constructs were used to further clarify differences in TGF1- and IL-1-induced HAS1 activation. Overexpressing IB completely abolished the IL-1 effect on HAS1 but did not interfere with TGF1-induced HAS1 mRNA accumulation. Identical results were obtained when a dominant negative IKK was overexpressed. Interestingly, neither overexpression of IB nor of IKK had any effect on HAS2 and HAS3 mRNA levels. Taken together, HAS1 can be activated by distinct pathways; IL-1 utilizes NF-B, and TGF1 does not. Furthermore, HAS2 and HAS3 are activated without the involvement of NF-B.

Received for publication, March 28, 2005 , and in revised form, August 2, 2005.

^* This work was supported in part by grants from the City of Vienna, the Austrian Ministry of Social Security and Generations, the Austrian Ministry of Education, Science and Culture, and the Austrian National Bank. 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.

¹ To whom correspondence should be addressed: Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, 1100 Vienna, Austria. Tel.: 43-1-68-00-99-231; Fax: 43-1-68-00-99-234; E-mail: karlms{at}excite.com.

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