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Published ahead of print on February 5, 2004, doi:10.1165/rcmb.2003-0380OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 1, July 2004, 92-99

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Submitted on October 24, 2003
Revised on February 5, 2004

Pro- and anti-inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts

Thomas S Wilkinson1, Susan Potter-Perigo1, Christina Tsoi1, Leonard C Altman2, and Thomas N Wight3*

1 Vascular Biology, The Hope Heart Institute, Seattle, WA, USA, 2 Vascular Biology, The Hope Heart Institute, Seattle, WA, USA; Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA, 3 Vascular Biology, The Hope Heart Institute, Seattle, WA, USA; Department of Pathology, University of Washington, Seattle, WA, USA

* To whom correspondence should be addressed. E-mail: twight{at}hopeheart.org.

Hyaluronan (HA) is an important constituent of the extracellular matrix and accumulates during inflammatory lung diseases like asthma. Little is known about the factors that regulate HA synthesis by lung cells. Accordingly, we investigated the effect of T-helper 1 (TH1) and 2 (TH2) cytokines and the anti-inflammatory agents fluticasone and salmeterol on HA synthesis in human lung fibroblasts. IL-1{beta} and TNF{alpha} were the most potent stimulators of HA synthesis and when combined, caused synergistic increases in HA accumulation. Time course analysis of HA accumulation and [3H]-glucosamine incorporation into HA demonstrated continued synthesis over the 24 hours of stimulation. Peak synthesis at 6-12 hours coincided with an increased proportion of high molecular weight HA. RT-PCR revealed that IL-1{beta} and TNF{alpha} induced hyaluronan synthase-2 mRNA three hours following stimulation and remained elevated throughout the 24-hour stimulation period. Fluticasone, inhibited IL-1{beta} and TNF{alpha} induced HA synthesis (44.5%) while salmeterol had no effect. When combined, fluticasone and salmeterol inhibited HA synthesis to a greater extent (85.2%). Further, fluticasone attenuated IL-1{beta} and TNF{alpha} stimulated hyaluronan synthase-2 mRNA and the addition of salmeterol cooperatively enhanced this inhibition. These results indicate that enhanced synthesis of HA by the pro-inflammatory cytokines IL-1{beta} and TNF{alpha} can be abrogated by specific corticosteroid and {beta}2-blocker combinations shown to be effective in the treatment of asthma.




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