Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils.

Abstract

SummaryThrombin stimulation of human platelets results in the release of a preformed proteinaceous human eosinophil (Eo)-chemotactic activity. By the use of different high-performance liquid chromatography techniques, two Eo-chemotactic polypeptides (EoCPs), tentatively termed EoCP-1 and EoCP-2, were purified to homogeneity. Upon SDS-PAGE analysis, these chemotaxins showed molecular masses near 8 kD. NH2-terminal amino acid sequence analysis revealed identical sequences for both EoCP-1 and EoCP-2, which are also identical to that of R.ANTES, a cytokine that structurally belongs to the interleukin 8 superfamily of leukocyte selective attractants, and that is known to be a "memory-type" T lymphocyte-selective attractant. In the major Eo chemotaxin, EoCP-1, the residues 4 and 5, which in EoCP-2 were found to be serine residues, could not be identified. Electrospray mass spectrometry (ESP-MS) of EoCPs revealed for EoCP-2 a molecular mass of 7,862.8 _+ 1.1 daltons, which is 15.8 mass units higher than the calculated value of RANTES, indicating that EoCP-2 is identical to the full-length cytokine, and oxygenation, probably at methionine residue number 64, has taken place. Upon ESP-MS, EoCP-1 showed an average molecular mass of 8,355 _+ 10 daltons, suggesting O-glycosylation at these serine residues. Both natural forms of RANTES showed strong Eo-chemotactic activity (EDs0 --2 nM) with optimal chemotactic migration at concentrations near 10 nM, however, there were no significant migratory responses with human neutrophils. Chemotactic activity of RANTES for human Eos could be confirmed using recombinant material, which has been found to be as active as the natural forms. Since R.ANTES gene expression has been detected in activated T lymphocytes, and recombinant RANTES was shown to be a "memory" T lymphocyte-selective attractant, it is now tempting to speculate about an important role of R.ANTES in clinical situations such as allergene-induced late-phase skin reactions in atopic subjects or asthma, where in affected tissues both memory T cells and Eos are characteristic.

Preferential transmission and association of the −403 G → A promoter RANTES polymorphism with atopic asthma

“…5 Increased production of RANTES would be expected to increase the level of inflammatory cell recruitment, as it is one of the major chemoattractant proteins for eosinophils 4 and others (basophils, mast cells and T lymphocytes) into asthmatic airways after allergen challenge. 21,22 The role of this particular pathway to immune regulation is also supported by observations that the GATA transcription motif in position 403 of the chemokine RANTES gene is associated with a number of inflammatory-mediated disease including rheumatoid arthritis 10 in delaying the progression of HIV infection, 23 and in the expression of childhood atopic dermatitis. 24 We have strengthened the evidence that this association is real by demonstrating familial transmission with asthma and atopy and by confirming that the association is predominantly toward atopy and atopic asthma.…”

The −403 G→A promoter polymorphism in the RANTES gene is associated with atopy and asthma

“…Indeed, linkage and molecular epidemiology studies have shown that several other such mediators (IL-4, IL-5, IL-13, interferon-␥) are candidates for susceptibility to asthma. [3][4][5] RANTES is produced by T-lymphocytes and monocytes and acts as a chemoattractant for several cell types (eg, mast cells, basophils, T-lymphocytes, eosinophils) 6,7 which are central to the inflammatory cascade. Therefore, increased production of RANTES would be predicted to result in enhanced recruitment of proinflammatory cells to the target site, precipitating an amplified local inflammatory reaction.…”

“…This mediator has the ability to attract several types of inflammatory cells including monocytes, eosinophils and memory Thelper (Th) cells to the site of inflammation. 6,7 Furthermore, increased levels of RANTES and other members of the C-C family of chemokines (MIP-1␣, MCP-1) have been detected in the nasal secretions of atopic patients exposed to local allergen challenge 8 and were found in higher levels in the bronchial lavage fluid of patients with active asthma. 9 RANTES has also been found at significantly higher levels in patients during asthma attacks than in those with asymptomatic stages or in controls.…”

RANTES Gene Promoter Polymorphisms Are Associated with Bronchial Hyperresponsiveness in Korean Children with Asthma

“…It is a potent chemoattractant for eosinophils, lymphocytes, monocytes, and basophils [3][4][5]. RANTES is expressed in activated T lymphocytes, airway epithelial cells, platelets, fibroblasts, and renal epithelial and mesangial cells [6].…”