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Neutrophil Dysfunction in Guanosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase I-Deficient Mice¹

Claudia G. Werner^2,*, Virginia Godfrey, Roland R. Arnold, Gerald L. Featherstone, Diane Bender, Jens Schlossmann^*, Matthias Schiemann, Franz Hofmann^* and Katherine B. Pryzwansky

^* Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany; Department of Pathology and Laboratory Medicine, and Dental Research Center, Department of Diagnostic Sciences, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599; and Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, München, Germany

The regulation of neutrophil functions by Type I cGMP-dependent protein kinase (cGKI) was investigated in wild-type (WT) and cGKI-deficient (cGKI^–/–) mice. We demonstrate that murine neutrophils expressed cGKI. Similar to the regulation of Ca²⁺ by cGKI in other cells, there was a cGMP-dependent decrease in Ca²⁺ transients in response to C5a in WT, but not cGKI^–/– bone marrow neutrophils. In vitro chemotaxis of bone marrow neutrophils to C5a or IL-8 was significantly greater in cGKI^–/– than in WT. Enhanced chemotaxis was also observed with cGKI^–/– peritoneal exudate neutrophils (PE-N). In vivo chemotaxis with an arachidonic acid-induced inflammatory ear model revealed an increase in both ear weight and myeloperoxidase (MPO) activity in ear punches of cGKI^–/– vs WT mice. These changes were attributable to enhanced vascular permeability and increased neutrophil infiltration. The total extractable content of MPO, but not lysozyme, was significantly greater in cGKI^–/– than in WT PE-N. Furthermore, the percentage of MPO released in response to fMLP from cGKI^–/– (69%) was greater than that from WT PE-N (36%). PMA failed to induce MPO release from PE-N of either genotype. In contrast, fMLP and PMA released equivalent amounts of lysozyme from PE-N. However, the percentage released was less in cGKI^–/– (60%) than in WT (90%) PE-N. Superoxide release (maximum velocity) revealed no genotype differences in responses to PMA or fMLP stimulation. In summary, these results show that cGKI down-regulates Ca²⁺ transients and chemotaxis in murine neutrophils. The regulatory influences of cGKI on the secretagogue responses are complex, depending on the granule subtype.

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