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Am J Physiol Cell Physiol 282: C1261-C1269, 2002; doi:10.1152/ajpcell.00479.2001
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Vol. 282, Issue 6, C1261-C1269, June 2002

Hypertonicity increases cAMP in PMN and blocks oxidative burst by PKA-dependent and -independent mechanisms

Tatjana Orlic, William H. Loomis, Amy Shreve, Sachiko Namiki, and Wolfgang G. Junger

Surgical Immunology Research Laboratory, Department of Surgery, Division of Trauma, University of California, San Diego, California 92103-8236

Hypertonic stress (HS) suppresses neutrophil (PMN) functions. We studied the underlying mechanism and found that HS rapidly (<1 min) increased intracellular cAMP levels by up to sevenfold. cAMP levels correlated with applied hypertonicity and the degree of neutrophil suppression. HS and cAMP-elevating drugs (forskolin and dibutyryl cAMP-acetoxymethyl ester) similarly suppressed extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase activation and superoxide formation in response to N-formylmethionyl-leucyl-phenylalanine (fMLP) stimulation. Inhibition of cAMP-dependent protein kinase A (PKA) with H-89 abrogated the suppressive effects of HS, restoring fMLP-induced ERK and p38 activation and superoxide formation. Inhibition of phosphodiesterase with 3-isobutyl-1-methylxanthine augmented cAMP accumulation and the suppressive effects of HS, while inhibition of adenylyl cyclase with MDL-12330A abolished these effects. These findings suggest that HS-activated cAMP/PKA signaling inhibits superoxide formation by intercepting fMLP-induced activation steps upstream of ERK and p38. In contrast to its effects in the presence of moderate hypertonicity levels (40 mM), H-89 was unable to rescue neutrophil functions from suppression by higher hypertonicity levels (100 mM), indicating that more severe HS suppresses neutrophils via secondary PKA-independent mechanisms.

inflammation; osmotic stimulation; signal transduction


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