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Prepublished online as a Blood First Edition Paper on April 24, 2003; DOI 10.1182/blood-2002-12-3771.
Submitted December 11, 2002
Accepted April 15, 2003
TGF inhibits LPS-induced chemokine mRNA stabilization
Yalei Dai, Shyamasree Datta, Michael Novotny, and Thomas A Hamilton*
Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH, USA
* Corresponding author; email: hamiltt{at}ccf.org.
The mechanisms involved in anti-inflammatory action of TGF have been examined by evaluating its effect on chemokine gene expression in mouse macrophages. LPS-stimulated expression of the CXC chemokines KC and MIP-2 was selectively reduced by TGF in a time- and protein synthesis-dependent process. While TGF had a modest effect on transcription of the KC and MIP-2 genes as measured by nuclear run-on, it had no effect on LPS-stimulated luciferase expression driven by the KC promoter nor on the activation of NF B DNA binding activity and transactivation function. Interestingly, KC mRNA levels were markedly reduced by TGF treatment in cells transfected with KC genomic or cDNA constructs driven from either the KC or cytomegalovirus (CMV) promoters demonstrating the importance of sequences within the mature mRNA and suggesting that suppression may involve a post-transcriptional mechanism. In support of this possibility, LPS stimulation prolonged the half-life of KC mRNA and this stabilization response was blocked in cells treated with TGF. Examination of KC mRNA expressed under control of a tetracycline-responsive promoter demonstrated that TGF prevented stabilization of KC mRNA in response to LPS but did not alter KC mRNA half-life directly. KC mRNA stabilization by LPS was dependent on activation of p38 mitogen activated protein kinase (MAPK) activity and TGF treatment inhibited p38 MAPK activation. These findings support the hypothesis that TGF-mediated suppression of chemokine gene expression involves antagonism of LPS-stimulated KC mRNA stabilization via inhibition of p38 MAPK.
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