Regulation of calcium homeostasis in activated human neutrophils--potential targets for anti-inflammatory therapeutic strategies.
OBJECTIVE
The objectives of the current study were to: (i) present an integrated model for the restoration of calcium homeostasis in activated human neutrophils based on current knowledge and recent research; and (ii) identify potential targets for the modulation of calcium fluxes in activated neutrophils based on this model and to investigate the effects of intracellular probes which target key processes involved in calcium homeostasis and pro-inflammatory activity in these cells.


METHODS
Laboratory-based experimental research using purified human neutrophils from healthy, adult human volunteers.


METHODS
Calcium metabolism and pro-inflammatory activity of neutrophils.


RESULTS
Modulation of calcium fluxes in activated human neutrophils can be achieved by cAMP-dependent upregulation of the activity of the endomembrane Ca(2+)-ATPase which resequesters cytosolic Ca2+. Formoterol, a long-acting beta 2-agonist, elevates intracellular cAMP levels, accelerates Ca2+ restoration in activated neutrophils and downregulates the pro-inflammatory responses of these cells. Alterations in the membrane potential of activated neutrophils may play a role in regulating calcium reuptake into the cells as attenuation of the membrane depolarisation response is associated with accelerated calcium influx.


CONCLUSIONS
Modulation of the activity of the endomembrane Ca(2+)-ATPase in human neutrophils represents an important target for anti-inflammatory
Tintinger
G R
GR
Department of Internal Medicine, University of Pretoria.
Anderson
R
R
Ker
J A
JA
D000318:Adrenergic beta-Agonists / Q000276:immunology / Q000494:pharmacology; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000276:immunology* / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D004983:Ethanolamines / Q000276:immunology / Q000494:pharmacology; D000068759:Formoterol Fumarate; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D018448:Models, Immunological; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000276:immunology / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D013256:Steroids
D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D004983:Ethanolamines; D013256:Steroids; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D000252:Calcium-Transporting ATPases; D002118:Calcium; D000068759:Formoterol Fumarate