Inhibitory effect of 3-caffeoyl-4-dicaffeoylquinic acid from Salicornia herbacea against phorbol ester-induced cyclooxygenase-2 expression in macrophages

Tonicity-responsive genes are regulated by the TonE enhancer element and the tonicity-responsive enhancer binding protein (TonEBP) transcription factor with which it interacts. Urea, a permeant solute coexistent with hypertonic NaCl in the mammalian renal medulla, activates a characteristic set of signaling events that may serve to counteract the effects of NaCl in some contexts. Urea inhibited the ability of hypertonic stressors to increase expression of TonEBP mRNA and also inhibited tonicity-inducible TonE-dependent reporter gene activity. The permeant solute glycerol failed to reproduce these effects, as did cell activators including peptide mitogens and phorbol ester. The inhibitory effect of urea was evident as late as 2 h after the application of hypertonicity. Pharmacological inhibitors of known urea-inducible signaling pathways failed to abolish the inhibitory effect of urea. TonEBP action is incompletely understood, but evidence supports a role for proteasome function and p38 action in regulation; urea failed to inhibit proteasome function or p38 signaling in response to hypertonicity. Consistent with its effect on TonEBP expression and action, urea pretreatment inhibited the effect of hypertonicity on expression of the physiological effector gene, aldose reductase. Taken together, these data 1) define a molecular mechanism of urea-mediated inhibition of tonicity-dependent signaling, and 2) underscore a role for TonEBP abundance in regulating TonE-mediated gene transcription.

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Taurolithocholate-induced Ca2+ release is inhibited by phorbol esters in isolated hepatocytes

Biochemical Journal ◽

10.1042/bj2870891 ◽

1992 ◽

Vol 287 (3) ◽

pp. 891-896 ◽

Cited By ~ 4

Author(s):

L Combettes ◽

B Berthon ◽

M Claret

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Phorbol Ester ◽

Phorbol Esters ◽

Rat Hepatocytes ◽

Isolated Hepatocytes ◽

Inhibitory Effect ◽

Cell Uptake ◽

Intracellular Binding ◽

Pkc Activation

The monohydroxy bile acid taurolithocholate (TLC) causes a rapid and transient increase in free cytosolic Ca2+ concentration ([Ca2+]i) in suspensions of rat hepatocytes similar to that elicited by the InsP3-dependent hormone vasopressin. The effect of the bile acid is due to a mobilization of Ca2+, independent of InsP3, from the endoplasmic reticulum (ER). Short-term preincubation of cells with the phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA), which activates protein kinase C (PKC), blocked the increase in [Ca2+]i induced by TLC, but did not alter that mediated by vasopressin. We obtained the following results, indicating that the effect of PMA is mediated by the activation of PKC. (1) Phorbol esters were effective over a concentration range where they activate PKC (IC50 = 0.5 nM); (2) phorbol esters that do not activate PKC did not inhibit the effects of TLC; (3) the permeant analogue oleoylacetylglycerol mimicked the inhibitory effect of PMA; (4) lastly, the inhibition of the TLC-induced Ca2+ mobilization by phorbol esters was partially prevented by preincubating the cells with the PKC inhibitors H7 and AMG-C16. Preincubating hepatocytes with PMA had no effect on the cell uptake of labelled TLC, indicating that the phorbol ester does not interfere with the transport system responsible for the accumulation of bile acids. In saponin-treated liver cells, PMA added before or after permeabilization failed to abolish TLC-induced Ca2+ release from the ER. The possibility is discussed that PMA, via PKC activation, may alter the intracellular binding or the transfer of bile acids in the liver.

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