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

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 Ca 2+ 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 by the 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.

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

“…This correlates with the induction of MKP-1 [15,16]. Moreover, conditions that block MKP-1 induction by M-CSF elongate ERK activity and inhibit proliferation [10,11]. This observation is supported by the finding that mice lacking MKP-1 have enhanced MAPK activity [48].…”

“…For proliferation, ERK must be dephosphorylated approximately 15 min after activation [9]. A number of conditions that elongate ERK activity, for example extracellular matrix proteins, such as decorin or fibrinogen, or treatment with cyclosporin A or FK506 reduce proliferation [10,11]. Recently, we have shown that inhibition of MAP kinase phosphotose-1 (MKP-1) expression using siRNA leads to elongated ERK phosphorylation and blockage of M-CSF-dependent proliferation [12].…”

Deacetylase Activity Is Required for STAT5-Dependent GM-CSF Functional Activity in Macrophages and Differentiation to Dendritic Cells

“…Our experiments show that genes regulated through these pathways are not affected by the inhibition of deacetylase activity. The activation of ERK1/2 is required for GM-CSF-and M-CSF-dependent macrophage proliferation (33,34). However, TSA did not affect M-CSF-dependent proliferation, which implies that genes that require the ERK pathway are not inhibited.…”

“…This observation also demonstrates that TSA, at the concentration used in our assays, did not induce cellular toxicity. Stimulation of macrophage proliferation by both M-CSF and GM-CSF requires the activation of extracellular signal-regulated kinases or ERKs (33,34). The observation that TSA did not affect M-CSFinduced proliferation indicates that this inhibitor/drug does not target ERKs.…”

Differential Expression of Cyclophilin A and EMMPRIN in Developing Molars of Rats

“…Cyp-A was originally discovered as an intracellular ligand for cyclosporin A, an immunosuppressant (Handschumacher et al, 1984), but other functions have also been suggested. The secreted form of Cyp-A is a potent chemoattractant for macrophage colony-stimulating factor (MCSF)-dependant macrophages (Comalada et al, 2003;Sà nchez-Tilló et al, 2006), monocytes (Galat, 1993;Payeli et al, 2008), neutrophils (Sherry et al, 1992), eosinophils (Xu et al, 1992), and T cells (Kasinrerk, 1999). This molecule is involved in the adhesion of monocytes/macrophages to the extracellular matrix (Yang et al, 2008) and the migration of murine bone marrow cells (Khromykh et al, 2007).…”