Tyrosine Kinase Inhibitors, Genistein and Herbimycin A, Do Not Block Interleukin-1 β-Induced Activation of NF-κB in Rat Mesangial Cells

1996 ◽  
Vol 218 (3) ◽  
pp. 808-812 ◽  
Author(s):  
Toshifumi Tetsuka ◽  
Sunil K. Srivastava ◽  
Aubrey R. Morrison
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Mesangial Cells ◽  
Interleukin 1 ◽  
Herbimycin A

Tyrosine kinase activation is necessary for inducible nitric oxide synthase expression by interleukin-1 beta

1995 ◽  
Vol 269 (1) ◽  
pp. C55-C59 ◽  
Author(s):  
T. Tetsuka ◽  
A. R. Morrison
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Mesangial Cells ◽  
Interleukin 1 ◽  
Inos Mrna ◽  
Nitrite Production ◽  
Oxide Synthase

The inflammatory cytokine interleukin-1 (IL-1) induces the inducible form of nitric oxide synthase (iNOS) with an increase in nitric oxide in rat mesangial cells. However, the cellular mechanisms that underlie the induction of iNOS by IL-1 beta in mesangial cells has not been clarified. Because we have shown that tyrosine kinase inhibitors attenuate IL-1 beta-induced cyclooxygenase expression and prostaglandin production, we investigated the effect of tyrosine kinase inhibitors on IL-1 beta-induced nitrite production and iNOS mRNA expression in rat mesangial cells. The tyrosine kinase inhibitors genistein and herbimycin A attenuated IL-1 beta-induced nitrite production in a dose-dependent manner. In addition, both of these inhibitors blocked IL-1 beta-induced iNOS mRNA expression. These data suggest that tyrosine kinase(s) plays a central role in IL-1 beta signaling to induce iNOS in rat mesangial cells.

Tyrosine kinase inhibitors block the glucocorticoid stimulation of prostaglandin endoperoxide H synthase expression in amnion cells

1999 ◽  
Vol 77 (2) ◽  
pp. 138-142 ◽  
Author(s):  
Tamas Zakar ◽  
Jane E Mijovic ◽  
Damyanti Bhardwaj ◽  
David M Olson
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Prostaglandin Endoperoxide ◽  
Herbimycin A ◽  
Cell Extracts ◽  
Endoperoxide H Synthase ◽  
Stimulation Of

Human amnion cells in primary culture respond to glucocorticoids in a characteristic fashion by the increased expression of the inducible prostaglandin endoperoxide H synthase isoenzyme, PGHS-2. Since PGHS-2 induction by agonists generally involves tyrosine kinases, we examined the possibility that the glucocorticoid stimulation of PGHS-2 in the amnion cells is tyrosine kinase dependent. PGHS-2 expression was stimulated in confluent, serum-starved amnion cells with dexamethasone, and the effect of the tyrosine kinase inhibitors herbimycin A and tyrphostins AG126, AG1288, and A1 on enzyme activity induction was determined. All four inhibitors blocked the increase of PGHS activity in a concentration-dependent manner with IC50 values of 0.077 ± 0.05, 15.38 ± 5.14, 20.91 ± 3.1, and 29.77 ± 8.21 µM, respectively (mean ± SE, n = 4). Dexamethasone increased (approximately twofold) the tyrosine phosphorylation of 120-, 110-, and 77-kDa proteins in cell extracts, and herbimycin A selectively blocked the phosphorylation of the 110-kDa phosphoprotein. The stimulation of the steady-state level of PGHS-2 mRNA by dexamethasone was also inhibited by herbimycin A. These results suggest that glucocorticoids induce PGHS-2 expression in amnion cells with the involvement of tyrosine kinase(s). The role of tyrosine kinase dependent mechanisms in the control of amnion cell responsiveness to corticosteroids remains to be established.Key words: amnion, glucocorticoid, tyrosine kinase, prostaglandin H synthase.

scholarly journals Integrin function: molecular hierarchies of cytoskeletal and signaling molecules.

1995 ◽  
Vol 131 (3) ◽  
pp. 791-805 ◽  
Author(s):  
S Miyamoto ◽  
H Teramoto ◽  
O A Coso ◽  
J S Gutkind ◽  
P D Burbelo ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Signaling Molecules ◽  
Cytochalasin D ◽  
Integrin Receptors ◽  
Jnk Pathway ◽  
Herbimycin A ◽  
Rapid Activation

Integrin receptors play important roles in organizing the actin-containing cytoskeleton and in signal transduction from the extracellular matrix. The initial steps in integrin function can be analyzed experimentally using beads coated with ligands or anti-integrin antibodies to trigger rapid focal transmembrane responses. A hierarchy of transmembrane actions was identified in this study. Simple integrin aggregation triggered localized transmembrane accumulation of 20 signal transduction molecules, including RhoA, Rac1, Ras, Raf, MEK, ERK, and JNK. In contrast, out of eight cytoskeletal molecules tested, only tensin coaccumulated. Integrin aggregation alone was also sufficient to induce rapid activation of the JNK pathway, with kinetics of activation different from those of ERK. The tyrosine kinase inhibitors herbimycin A or genistein blocked both the accumulation of 19 out of 20 signal transduction molecules and JNK- and ERK-mediated signaling. Cytochalasin D had identical effects, whereas three other tyrosine kinase inhibitors did not. The sole exception among signaling molecules was the kinase pp125FAK which continued to coaggregate with alpha 5 beta 1 integrins even in the presence of these inhibitors. Tyrosine kinase inhibition also failed to block the ability of ligand occupancy plus integrin aggregation to trigger transmembrane accumulation of the three cytoskeletal molecules talin, alpha-actinin, and vinculin; these molecules accumulated even in the presence of cytochalasin D. However, it was necessary to fulfill all four conditions, i.e., integrin aggregation, integrin occupancy, tyrosine kinase activity, and actin cytoskeletal integrity, to achieve integrin-mediated focal accumulation of other cytoskeletal molecules including F-actin and paxillin. Integrins therefore mediate a transmembrane hierarchy of molecular responses.

Tyrosine kinase involvement in IL-1 beta-induced expression of iNOS by beta-cells purified from islets of Langerhans

1994 ◽  
Vol 267 (1) ◽  
pp. C48-C54 ◽  
Author(s):  
J. A. Corbett ◽  
G. Kwon ◽  
T. P. Misko ◽  
C. P. Rodi ◽  
M. L. McDaniel
Keyword(s):  
Nitric Oxide ◽  
Tyrosine Kinase ◽  
Beta Cells ◽  
Kinase Inhibitors ◽  
Interleukin 1 ◽  
Inos Mrna ◽  
Rinm5f Cells ◽  
Mrna Accumulation ◽  
Induced Expression ◽  
Herbimycin A

Nitric oxide is believed to mediate the inhibitory effects of cytokines on glucose-stimulated insulin secretion by both rat and human islets. The aims of this study were 1) to determine the cellular source of the cytokine-inducible isoform of nitric oxide synthase (iNOS) expressed in islets following cytokine stimulation and 2) to determine whether tyrosine kinase activity participates in cytokine-induced iNOS expression. In this report we demonstrate that the cytokine interleukin-1 beta (IL-1 beta) stimulates the expression of iNOS and the formation of nitric oxide (as determined by nitrite formation, a stable oxidative product of nitric oxide) by isolated intact rat islets and by primary beta-cells purified by fluorescence-activated cell sorting (FACS). Both the expression of iNOS and nitrite formation induced by IL-1 beta were prevented by the mRNA transcriptional inhibitor actinomycin D. IL-1 beta did not induce the expression of iNOS by FACS-purified alpha-cells, the other major endocrine cell type of the islet. The tyrosine kinase inhibitors genistein and herbimycin A prevented IL-1 beta-induced expression of immunoprecipitable iNOS and nitrite release by islets, by insulinoma RINm5F cells, and by FACS-purified beta-cells. Herbimycin A and genistein also prevented IL-1 beta-induced iNOS mRNA accumulation as determined by Northern blot analysis of total RNA isolated from RINm5F cells. These findings indicate tyrosine kinase activation participates in IL-1 beta-induced expression of iNOS by the insulin-secreting beta-cell.(ABSTRACT TRUNCATED AT 250 WORDS)

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