Isolation of the CXC chemokines ENA‐78, GROα and GROγ from tumor cells and leukocytes reveals NH2‐terminal heterogeneity

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Abstract
Chemokines are a family of chemotactic peptides affecting leukocyte migration during the inflammatory response. Post‐translational modification of chemokines has been shown to affect their biological potency. Here, the isolation and identification of natural isoforms of the neutrophil chemoattractants GROα and GROγ and the epithelial‐cell‐derived neutrophil attractant‐78 (ENA‐78), is reported. Cultured tumor cells produced predominantly intact chemokine forms, whereas peripheral blood monocytes secreted mainly NH2‐terminally truncated forms. The order of neutrophil chemotactic potency of these CXC chemokines was GROα > GROγ > ENA‐78 both for intact and truncated forms. However, truncated GROα(4,5,6‐73), GROγ(5‐73) and ENA‐78(8,9‐78) were 30‐fold, fivefold and threefold more active than the corresponding intact chemokine. As a consequence, truncated GROα(4,5,6‐73) was 300‐fold more potent than intact ENA‐78 indicating that both the type of chemokine and its mode of processing determine the chemotactic potency. Similar observations were made when intact and truncated GROα, GROγ and ENA‐78 were compared for their capacity to induce an increase in the intracellular calcium concentration in neutrophilic granulocytes, and to desensitize the calcium response towards the CXC chemokine granulocyte chemotactic protein‐2 (GCP‐2). It must be concluded that physiological proteolytic cleavage of CXC chemokines in general enhances the inflammatory response, whereas for CC chemokines NH2‐terminal processing mostly results in reduced chemotactic potency.

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