Abstract
The capacity of neutrophils to generate superoxide (O-2) can be enhanced by prior exposure to "priming" agents such as interleukin-8 (IL-8), melanoma growth-stimulatory activity (MGSA), and neutrophil-activating peptide (ENA-78). The biological effects of these chemokines are mediated by at least two distinct receptors: type A (IL-8-RA) and type B (IL-8-RB). Using neutralizing monoclonal antibodies to IL-8-RA and IL-8-RB, we have investigated the contribution each receptor makes to the priming response. Preincubation with IL-8, MGSA, or ENA-78 enhanced the ability of neutrophils to generate O-2 following stimulation with the bacterial peptide formyl-Met-Leu-Phe. The priming effect of IL-8 was eliminated by an anti-IL-8 monoclonal antibody (mAb) that is known to bind IL-8 with high affinity and prevent receptor occupancy. Incubation of neutrophils with a neutralizing mAb specific for IL-8-RA blocked IL-8-induced priming but had no effect on priming by MGSA or ENA-78. In contrast, treatment with a neutralizing mAb specific for IL-8-RB failed to inhibit the priming effect of IL-8 but blocked both MGSA and ENA-78-induced priming. These observations indicate that the priming effect of IL-8 on the neutrophil respiratory burst is predominantly mediated via IL-8-RA, whereas priming by MGSA and ENA-78 is mediated by IL-8-RB.
Highlights
One of the primary roles of neutrophils is to provide the body with an efficient defense mechanism against microorganisms
Incubation of human neutrophils with 1 nM IL-8, melanoma growth-stimulatory activity (MGSA), or ENA-78 at 37 °C rapidly enhanced the ability of FMLP to trigger a respiratory burst (Fig. 1)
Incubation of neutrophils with 1 nM IL-8, MGSA, and ENA-78 for 10 min at 37 °C enhanced the FMLP-triggered respiratory burst from 14 Ϯ 2 to 41 Ϯ 5, 33 Ϯ 7, and 33 Ϯ 3 nmol/min/107 cells, respectively (Fig. 2), indicating that these chemokines mediate priming via a high affinity interaction with IL-8 receptors
Summary
O2., superoxide; IL-8, interleukin-8; MGSA, melanoma growth-stimulatory activity; ENA-78, neutrophil activating peptide; mAb, monoclonal antibody; IL-8-RA, IL-8 receptor A; IL-8-RB, IL-8 receptor B; FMLP, formyl-Met-Leu-Phe; PBS, phosphatebuffered saline. Exposure of neutrophils to IL-8, MGSA, or ENA-78 induces a wide range of biological responses including an intracellular calcium flux, changes in intracellular pH, chemotaxis, cytoskeleton reorganization, and shape change (6, 14 –21). These responses are likely to be required to attract neutrophils to the site of inflammation and activate them for efficient microbial killing. Both receptors bind IL-8 with high affinity (1–2 nM); in contrast to IL-8-RA, IL-8-RB binds other CXC chemokines including MGSA, ENA-78, and neutrophil-activating peptide-2 with high affinity [14, 15, 22]. Using mAbs that bind to the IL-8 type A or B receptors and prevent ligand binding, we have determined the contribution each receptor makes to the priming response
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