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
- 13 October 2003
- journal article
- Published by Wiley in European Journal of Immunology
- Vol. 33 (11), 3091-3100
- https://doi.org/10.1002/eji.200324074
Abstract
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.Keywords
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