Macrophage colony-stimulating factor-dependent macrophage proliferation is mediated through a calcineurin-independent but immunophilin-dependent mechanism that mediates the activation of external regulated kinases.
Calcineurin is constitutively expressed in bone marrow-derived macrophages. However, macrophage response to macrophage colony-stimulating factor (M-CSF) was not impaired by the use of either calcineurin inhibitors (W-13, chlorpromazine and trifluoperazine), calcium chelators (BAPTA-AM) or Ca2+ channel antagonists (verapamil, nifedipine and diltiazem). Inhibition of calcineurin expression by inhibitory antisense RNA treatment did not result in an inhibition of M-CSF-dependent proliferation. Only very high doses of cyclosporin A and FK506 inhibited macrophage proliferation induced by growth factors, such as M-CSF, granulocyte-macrophage (GM)-CSF or IL-3. This inhibitory action is mediated by the peptidylprolyl isomerase activity of the immunophilins, as demonstrated bythe use of specific inhibitors (rapamycin and sanglifehrin A). These isomerase inhibitors exerted a negative effect on a key element involved in macrophage proliferation, namely the M-CSF-dependent activation of the extracellular signal-regulated kinases (ERK). In summary, the data presented here provide new insights in the mechanism of macrophage proliferation, which may have relevant consequences. First, we showed that in M-CSF-dependent proliferation calcineurin is not involved, and second, that immunophilins play a key role and their activation blocks ERK activation.
Comalada
Monica
M
Group of Macrophage Biology, Biomedical Research Institute of Barcelona, Barcelona Science Park, University of Barcelona, Barcelona, Spain.
Valledor
Annabel F
AF
Sanchez-Tilló
Ester
E
Umbert
Ignacio
I
Xaus
Jordi
J
Celada
Antonio
A
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D020104:Immunophilins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology
D007166:Immunosuppressive Agents; D007783:Lactones; D013141:Spiro Compounds; C121329:sanglifehrin A; D016173:Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin; D020104:Immunophilins; D020123:Sirolimus