[Modulation of the oxidative burst of human neutrophils by pro- and anti-inflammatory cytokines].
Human polymorphonuclear neutrophils (PMN) and cytokines play a critical role in host defences against invading microorganisms. In response to a variety of stimuli, PMN are a major source of reactive oxygen species (ROS) which are essential for bacterial killing and may induce oxidative stress in tissue environment. A precise regulation of the oxidase activity is therefore necessary. Cytokines such as TNF alpha, GM-CSF, IL-8, IL-6, IL-1 alpha and IL-1 beta produced during the immune and inflammatory responses to pathogens have been reported to interact with PMN activities. However, contradictory results have been reported on their direct and priming effects on the PMN release of ROS (oxidative burst). We have used a flow cytometry method to study the effects of these cytokines on the oxidative burst of PMN in whole blood, in order to avoid PMN activation related to isolation procedures. None of the cytokines tested directly activated the PMN oxidative burst, but they did have differential priming effects on the oxidative burst in response to N-formyl peptides. TNF, GM-CSF and IL-8 strongly primed a subpopulation of PMN to produce H2O2 in response to fMLP, while IL-1 alpha, IL-1 beta and IL-6 failed to do so. Furthermore, the addition of TNF, GM-CSF or IL-8 to whole blood increased the capacity of a subpopulation of PMN to bind N-formyl peptides, a phenomenon that could account for the strong H2O2 production in response to fMLP following priming by the cytokines. These results show that, among the various cytokines tested, TNF, GM-CSF and IL-8 strongly prime the PMN oxidative burst in response to bacterial peptides in whole blood and suggest that these cytokines may play a critical role in bacterial killing in vivo and also in the surrounding tissue injury secondary to pathological inflammatory reactions. In particular, TNF and IL-8 plasma levels as well as LPS-induced monocytic production of these cytokines ex vivo have been correlated with the production of ROS by stimulated PMN and with the lung injury score in patients with Adult Respiratory Distress Syndrom (ARDS). However, desensitization phenomena have also been described. In particular, in HIV infected patients we demonstrated a decrease of H2O2 production by PMN in whole blood after ex vivo priming by IL-8 and TNF followed by fMLP stimulation. This decrease increased with the progression of the disease and was inversely correlated with IL-8 plasma level. Different mechanisms could explain such desensitization phenomena at the receptor and post receptor level. In addition cytokines are involved in a complex network of regulation and anti inflammatory cytokines, such as IL-10, could act as a negative signal on the proinflammatory cytokines induced-priming of oxidative burst.
Gougerot-Podicalo
M A
MA
Laboratoire d'Immunologie et d'Hématologie et INSERM U. 294, CHU X. Bichat, Paris.
Elbim
C
C
Chollet-Martin
S
S
D016207:Cytokines / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D016209:Interleukin-8 / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects*; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006861:Hydrogen Peroxide
Modulation de l'explosion oxydative des polynucléaires neutrophiles humains par les cytokines pro- et anti-inflammatoires.