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Vol. 63, Issue 5, 1104-1116, May 2003
1-Adrenergic Receptor
Subtypes by Oligonucleotide Microarrays: Coupling to Interleukin-6
Secretion but Differences in STAT3 Phosphorylation and gp-130
Department of Molecular Cardiology, Lerner Research Institute,
Cleveland Clinic Foundation, Cleveland, Ohio
1-Adrenoceptor subtypes (1A-,
1B-, 1D-) are known to couple to similar
signaling pathways, although differences among the subtypes do exist.
As a more sensitive assay, we used oligonucleotide microarrays to
identify gene expression changes in Rat-1 fibroblasts stably expressing
each individual subtype. We report the gene expressions that change by
at least a factor of 2 or more. Gene expression profiles significantly
changed equally among all three subtypes, despite the unequal efficacy
of the inositol phosphate response. Gene expressions were clustered
into cytokines/growth factors, transcription factors, enzymes, and
extracellular matrix proteins. There were also a number of individual
subtype-specific changes in gene expression, suggesting a link to
independent pathways. In addition, all three 1-AR
subtypes robustly stimulated the transcription of the prohypertrophic
cytokine interleukin (IL)-6, but differentially altered members of the
IL-6 signaling pathway (gp-130 and STAT3). This was confirmed by
measurement of secreted IL-6, activated STAT3, and gp-130 levels.
Activation of STAT3 Tyr705 phosphorylation by the 1-ARs
was not through IL-6 activation but was synergistic with IL-6,
suggesting direct effects. Interestingly, 1B-AR
stimulation caused the dimerization-dependent phosphorylation of Tyr705
on STAT3 but did not activate the transcriptional-dependent phosphorylation of Ser727. The 1B-AR also constitutively
down-regulated the protein levels of gp-130. These results suggest that
the 1B-AR has differential effects on the
phosphorylation status of the STAT3 pathway and may not be as
prohypertrophic as the other two subtypes.
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