Activated granulocytes oxidize the endogenous stem cell inhibitory peptide pGlu-Glu-Asp-Cys-Lys (pEEDCK) to the stimulatory dimer: a redox-mediated mechanism for demand-induced hematopoietic regulation.

We have previously shown that the pentapeptide pGlu-Glu-Asp-Cys-Lys (pEEDCK), which is associated with mature leukocytes, maintains pluripotent hematopoietic stem cells (colony-forming units-spleen [CFU-S]) in a quiescent state under physiological conditions. It is also known that its oxidation product, the disulfide-bonded homodimer (pEEDCK)2, is a growth factor for CFU-S in vivo. In this paper we report on the combined actions of the monomer and dimer in inducing rapid changes in stem cell proliferation in vivo. A single injection of 20 microg/kg synthetic dimer into mice stimulated CFU-S proliferation (60% in S-phase after 9-11 hours) and population expansion. Stimulated CFU-S traversed one cell cycle, with an estimated S-phase time of 5.5 hours, and then become quiescent again. Proliferation of CFU-S in response to dimer showed no sensitivity to the inhibitory effects of monomeric pEEDCK, whereas CFU-S proliferation did display sensitivity to inhibition after injection of cytosine arabinoside or doxorubicin. Products of mature granulocytes undergoing an oxidative burst reaction rapidly oxidized monomeric pEEDCK to the dimer. The suppressive effect of endogenous pEEDCK monomer on stem cell proliferation was thus converted within minutes to a stimulatory signal (dimer). Because many in vivo situations (e.g., infection) requiring increased hematopoiesis involve granulocyte and macrophage activation, the formation of dimer from endogenous pEEDCK monomer may provide an almost instantaneous demand-induced emergency signal for increasing stem cell proliferation and blood cell production.