Eosinophilotactic Tetrapeptides

Eosinophilotactic Tetrapeptides

Definition
Eosinophilotactic tetrapeptides exhibit peak in vitro chemotactic activity for human eosinophils and rapidly deactivate eosinophils to homologous and other stimuli at concentrations as low as 10 -10 M 1.

Related Peptides
The ECF-A acidic tetrapeptides Val-Gly-Ser-Glu, Ala-Gly-Ser-Glu and the analogue Val-Gly-Asp-Glu are selectively chemotactic for human eosinophils over a narrow dose range. Histamine abrogates the chemotactic properties of the individual tetrapeptides 2.

Discovery
The eosinophil chemotactic factor of anaphylaxis, ECF-A, was discovered in 1971 by Kay et al., as a mediator released during immediate-type hypersensitivity reactions in guinea pig and human lung slices 1.

Structural Characteristics
Two eosinophilotactic tetrapeptides of amino acid sequence Val-Gly-Ser-Glu and Ala-Gly-Ser-Glu were recovered from the extracts in 4-12% overall yield of the low molecular weight peak from Sephadex G-25. Purified eosinophil chemotactic factor of anaphylaxis and the synthetic tetrapeptides were maximally active in a chemotactic chamber, and the activity was dependent on both the NH2 terminal and the COOH-terminal residues. Both natural and synthetic peptides were preferentially chemotactic for eosinophils and rendered them unresponsive to a subsequent stimulus1.

Mode of Action
The chemotactic activity of the tetrapeptide is dependent on both the hydrophobic NH2-terminal residue, which interacts with a hydrophobic domain in the chemotactic receptor, and the highly-charged COOH-terminal residue which is presumed to initiate eosinophil movement by perturbing a polar domain in the same receptor. The spatial requirement for effective interaction with both domains in the receptor is revealed by the lower potency and activity of the condensed tripeptides lacking glycine. The 10-fold greater potency of NH2-terminal tripeptide compared to the amide derivatives of NH2-terminal amino acids in reversibly inhibiting the intact tetrapeptides suggests a role for serine in binding to a portion of the receptor, possibly by hydrogen bonding. The COOH-terminal substituent tripeptide irreversibly suppresses eosinophil chemotaxis by a cell-directed action possibly reflecting its capacity to perturb the polar domain; this effect, resembling de-activation, requires higher concentrations than needed for deactivation by the tetrapeptide 3.



Functions
ECF-A was discovered in 1971 as the mediator that is responsible for most of the eosinophil chemotactic activitv released during anaphylactic reactions. Of the other mediators of immediate hypersensitivity, only histamine stimulates directed migration of eosinophils in vitro; however, its action is transient and lacks apparent in vivo chemotactic activity 4.



References
1. Goetzl EJ, Austen KF (1975). Purification and synthesis of eosinophilotactic tetrapeptides of human lung tissue: Identification as eosinophil chemotactic factor of anaphylaxis (leukocyte chemotaxis/leukocyte deactivation/ anaphylactic mediators/acidic peptides of lung). PNAS., 72(10):4123-4127.
2. Turnbull LW, Evans DP, Kay AB (1977). Human eosinophils, acidic tetrapeptides (ECF-A) and histamine. Interactions in vitro and in vivo. Immunology, 32(1):57-63.
3. Goetzl EJ, Austen KF (1976). Structural determinants of the eosinophil chemotactic activity of the acidic tetrapeptides of Eosinophil Chemotactic Factor of Anaphylaxis. J Exp Med., 144:1424-1437.
4. Goetzl EJ (1976). Modulation of human eosinophil polymorphonuclear leukocyte migration and function. Am J Pathol., 85(2):419-436.

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