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Human MPF (Lys-Lys-Gly-Glu) stimulates the proliferative response of human lymphocytes to the T-cell mitogen concanavalin A by 121-751% in the concentration range 10(-11)-10(-4) M; the peak effect is at 10(-8) M, lower or higher concentrations eliciting reduced responses, i.e. the dose-response curve is bell-shaped. Species specificity is high. Human MPF similarly stimulates rat lymphocytes, but the peak effect is seen at a 100-fold higher dose (10(-6) M). Rat MPF (Lys-Lys-Gly-Gln) has a peak effect at 10(-6) M with human lymphocytes, but the peak effect with rat lymphocytes is at a 1000-fold lower dose (10(-9) M). Truncated forms of the MPFs (Gly-Glu, Gly-Gln, Gly, Glu, Gln) and opioid peptides (beta-endorphin, [Leu] and [Met]enkephalin) show insignificant or only weak stimulatory or inhibitory effects. These results suggest that MPF acts via specific non-opioid receptors located on lymphocytes and that endogenously released MPF may have an important role in the functioning of the immune system.

The ability of newts and other urolele amphibians to regenerate an accidentally-removed or amputated limb is lost after hypophysectomy, but restored following intraperitoneal injection of beta endorphin, or the C-terminal tetrapeptide sequence of human beta endorphin, Lys-Lys-Gly-Glu (= MPF). The closely related tetrapeptide, Lys-Lys-Gly-Gln (the C-terminal sequence of pig, sheep, and camel beta endorphin), the dipeptide Gly-Glu, the enkephalins, and other N-terminal sequences of beta endorphin (eg gamma endorphin) do not elicit the effect.

The ability of B-endorphin to initiate limb regeneration in hypophysectomised newts is confined to the human species of the peptide and is contained in its C-terminal tetrapeptide sequence, Lys-Lys-Gly-Glu (MPF). Results with fifteen MPF analogs show that: (a) small structural change at the C-terminal Glu residue destroys activity, (b) at the Gly position, change of -NH-CH2-CO by -NH-NH-CO- (Azgly) or -NH-CHMe-CO- (Ala) also destroys the activity, but methylation of the NH results in an analog (Sar) with good activity, (c) analogs in which the Lys residues are replaced by D-Lys, Nle or Orn may retain some activity, particularly when the second Lys is replaced by D-Lys, and (d) the activity is retained or increased by N-terminal acylation. By combining 'favourable' changes, an analog acetyl-Lys-D-Lys-Sar-Glu was devised which was 1.25 times more potent than MPF, and metabolically more stable.