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*
Department of Biochemistry, Imperial College of Science, Technology and Medicine, London, United Kingdom, and Cortecs, Clwyd, United Kingdom; and
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Recently, it has emerged that extracellular proteases have specific
regulatory roles in modulating immune responses. Proteases may act as
signaling molecules to activate the Raf-1/extracellular regulated
kinase (ERK)-2 pathway to participate in mitogenesis, apoptosis, and
cytokine production. Most reports on the role of protease-mediated cell
signaling, however, focus on their stimulatory effects. In this study,
we show for the first time that extracellular proteases may also block
signal transduction. We show that bromelain, a mixture of cysteine
proteases from pineapple stems, blocks activation of ERK-2 in Th0 cells
stimulated via the TCR with anti-CD3
mAb, or stimulated with
combined PMA and calcium ionophore. The inhibitory activity of
bromelain was dependent on its proteolytic activity, as ERK-2
inhibition was abrogated by E-64, a selective cysteine protease
inhibitor. However, inhibitory effects were not caused by nonspecific
proteolysis, as the protease trypsin had no effect on ERK activation.
Bromelain also inhibited PMA-induced IL-2, IFN-
, and IL-4 mRNA
accumulation, but had no effect on TCR-induced cytokine mRNA
production. This data suggests a critical requirement for ERK-2 in
PMA-induced cytokine production, but not TCR-induced cytokine
production. Bromelain did not act on ERK-2 directly, as it also
inhibited p21ras activation, an effector
molecule upstream from ERK-2 in the Raf-1/MEK/ERK-2 kinase signaling
cascade. The results indicate that bromelain is a novel inhibitor of T
cell signal transduction and suggests a novel role for extracellular
proteases as inhibitors of intracellular signal transduction
pathways.
This article has been cited by other articles:
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