GM‐CSF and phorbol esters modulate GM‐CSF receptor expression by independent mechanisms

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Abstract
Human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) (0.1 nM) down‐modulates its receptor in IL‐3/GM‐CSF dependent M‐07e cells, in KG‐1 cells and normal granulocytes, whereas phorbol esters 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) (2 nM) down‐modulates the GM‐CSF receptor in M‐07e cells and granulocytes but not in KG‐1 cells. As data analysis shows by nonlinear regression, the decreased binding ability depends on a reduction of the binding sites with no significant change of their dissociation constant. To gain insight into the mechanisms involved in the GM‐CSF receptor regulation, we investigated the role of protein kinase C (PKC). GM‐CSF, unlike TPA, was unable to activate PKC in all the cells studied. Moreover, unlike TPA, GM‐CSF was still able to down‐modulate its receptor in cells where PKC was inhibited by 1‐(5‐isoquinolonesulphonyl)‐2‐methylpiperazine (H7) and staurosporine or in cells where PKC was exhausted by prolonged incubation with 1 μM TPA. Finally, the receptor re‐expression rate was accelerated by protein kinases inhibitors. These results, taken together, indicate the presence of a PKC‐dependent and ‐independent down‐modulation mechanism and a negative role of the endogeneous protein kinases in GM‐CSF receptor re‐expression.

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