A great body of evidence has accumulated that the human neutrophil is both a target and a source of various proinflammatory cytokines, chemokines, and growth factors, and therefore often exerts its proinflammatory functions through an autoregulatory pathway. Neutrophils are exquisite targets of proinflammatory cytokines, eg, IL-1 and TNF- a, of chemokines such as IL-8, and growth factors such as granulocyte/ monocyte colony stimulating factor (G-CSF and GM-CSF). Indeed, these cytokines have been shown to amplify several functions of neutrophils, including their capacity of adhering to endothelial cells and to pro-duce ROS, as described above; likewise, chemokines act as potent attractants and favor their orientated migration toward the inflammatory site. An important issue is that both cytokines and chemokines may also act as priming agents of neutrophils.
Indeed, neutrophils were long considered to be devoid of transcriptional activity and capable of performing no or little protein synthesis. However, convincing molecular evidence has now been afforded that neutrophils either constitutively or in an inducible manner can synthesize and release a wide range of proinflammatory cytokines, antiinflammatory cytokines, and other cytokines and growth factors (Table 1). The production of cytokines by activated neutrophils is striking in its diversity. However, it remains much lower in its degree than that produced by the mononuclear phagocytes, namely the monocytes. This important dis-crepancy between the two cell types leads to the use of extremely purified neutrophil preparations when studying their cytokine production.
Table 1: Cytokines expression by Neutrophils in Vitro
|Cytokines Type||Expressed by Neutrophils in Vitro|
|Anti-inflammatory cytokines||IL-1 receptor antagonist (IL-1Ra)|
|Growth-realted gene product-α (GRO-α)|
|Macrophage infiltrating protein-1α (MCP-1α)|
|Macrophage infiltrating protein-1β (MCP-1β)|
|Cytokine-induced chemoattractants (CINC)|
|Other cytokines and growth factors||Interferon-α (IFN-α), IFN-β|
|Granulocyte colony-stimulating factor (G-CSF)|
|Fas ligand (FasL), CD30 ligand (CD30L)|
|Vascular endothelial growth factor (VEGF)|
|Hepatocyte frowth factor (HGF)|
|Release under certain conditions||Macrophage-CSF (M-CSF), IL-3, GRO-β|
|IL-18 (IFN-γ inducible factor)|
|Oncostain (OSM) and neurotrophins|
|Secretion still debated||IL-6, monocyte chemotactoc protein-1 (MCP-1)|
|granulocyte-macrophage CSF (GM-GSF)|
|stem cell factor (SCF), IFN-γ|
However, this appears less evident in vivo if one considers that (i) the number of circulating neutrophils is almost 20 times higher than that of monocytes, and (ii) at the site of inflammation, neutrophils are the first to be recruited and largely predominate over monocytes. The production of cytokines is also largely influenced by the stimulating agents and among these, cytokines and bacterial endotoxins (LPS) are the most potent inducers (Table 2). The pattern of cytokines produced by neutrophils also greatly differs depending on the ag-onist, and for some cytokines co-stimulation by at least two of agonists is required, eg, IFN- g 1 LPS in the case of IL-12. Another important feature is that cytokine production is pre ceded by a consistent accumulation of the corresponding mRNA cytokines. Finally, the production of cytokines by neutrophils can easily be modulated by immunomodulatory cytokines such as IFN- g, IL-4, IL-10, and IL-13, suggesting that T helper-1 (Th-1) or Th-2 cells may influence neutrophil cytokine production.