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Vol. 298, Issue 1, 77-85, July 2001
and B1
Agonist Occurs through Independent and Synergistic Intracellular
Signaling Mechanisms in Human Lung Fibroblasts
Developmental Biology Program, Department of Surgery, Childrens
Hospital Los Angeles Research Institute, Los Angeles, California
(S.B.P., K.R., K.D.A., D.W.); and Department of Biochemistry, The
University of Texas Health Science Center, San Antonio, Texas
(L.M.F.L.-L.)
Bradykinin B1 receptors (B1R) are rapidly induced after tissue trauma
and are thought to be involved in maintaining the inflammatory response. Little is known about the intracellular signaling pathways mediating B1R induction in response to stress and inflammation. Here,
we show that up-regulation of B1R by B1R agonist and interleukin-1
(IL-1
) occur through distinct but synergistic pathways in IMR-90 human lung fibroblasts. Incubation of cells with the B1R agonist desArg10kallidin (desArg10KD; 100 nM) and
IL-1
(500 pg/ml) resulted in a 3- and 4-fold increase, respectively,
in B1R by 6 h, whereas coincubation of these factors produced up
to a 20-fold increase. Furthermore, coincubation increased the potency
of IL-1
by 2-fold. Both the individual and the synergistic responses
were sensitive to genistein, a general tyrosine kinase inhibitor. On
the other hand, only the desArg10KD response and the
synergistic response were sensitive to the p38 mitogen-activated
protein kinase inhibitor SB 203580. Furthermore, only the synergistic
response was sensitive to the nuclear factor-
B inhibitor pyrrolidine
dithiocarbamate. Despite B1R up-regulation in A549 human lung
epithelial cells by desArg10KD or IL-1
individually,
these factors did not act synergistically in this cell line. In
conclusion, our results reinforce the view that kinins act in concert
with proinflammatory cytokines to enhance selectively the inflammatory
response of certain lung cells to kinins through distinct but
synergistic intracellular signaling mechanisms. Thus, kinins may exert
a pivotal role in maintaining and modulating feed-forward inflammatory
processes in the lung.
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