Attenuation of haptoglobin gene expression by TGFbeta requires the MAP kinase pathway.
In addition to important roles in the regulation of cell growth and cell restitution, both pro- and anti-inflammatory effects have been ascribed to TGFbeta in intestinal epithelial cells. However, the mechanisms involved in TGFbeta-dependent anti-inflammatory activities remain to be determined. In the rat intestinal epithelial cell line IEC-6, TGFbeta attenuated the glucocorticoid-dependent increases in mRNA levels of the acute phase protein gene haptoglobin, and of C/EBP isoforms beta and delta. Supershift assays demonstrated a TGFbeta-mediated decrease in the binding of C/EBP isoforms beta and delta to the haptoA and haptoC C/EBP DNA-binding sites from the haptoglobin promoter. Mutations of both HaptoA and HaptoC sites abolished the glucocorticoid-dependent activation and the TGFbeta-mediated attenuation of the haptoglobin promoter, as assessed by transient transfection assays. TGFbeta induced p42/p44 MAP kinase activities. Treatment with the MEK 1/2 inhibitor PD 98059 abolished TGFbeta attenuation. These results suggest that C/EBP isoforms are involved both in the glucocorticoid-dependent induction and in the TGFbeta-mediated attenuation of haptoglobin expression. Furthermore, p42/p44 MAP kinases may function in a TGFbeta-dependent signaling pathway leading to attenuation of haptoglobin expression.
Yu
S J
SJ
Département d'anatomie et biologie cellulaire, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
Boudreau
F
F
Désilets
A
A
Houde
M
M
Rivard
N
N
Asselin
C
C
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005938:Glucocorticoids; D006242:Haptoglobins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one