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Sites of Action of Protein Kinase C and Phosphatidylinositol 3-Kinase Are Distinct in Oxidized Low Density Lipoprotein-induced Macrophage Proliferation*

Open AccessPublished:February 25, 2000DOI:https://doi.org/10.1074/jbc.275.8.5810
      Oxidized low density lipoprotein (Ox-LDL) can induce macrophage proliferation in vitro. To explore the mechanisms involved in this process, we reported that activation of protein kinase C (PKC) is involved in its signaling pathway (Matsumura, T., Sakai, M., Kobori, S., Biwa, T., Takemura, T., Matsuda, H., Hakamata, H., Horiuchi, S., and Shichiri, M. (1997) Arterioscler. Thromb. Vasc. Biol. 17, 3013–3020) and that expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) and its subsequent release in the culture medium are important (Biwa, T., Hakamata, H., Sakai, M., Miyazaki, A., Suzuki, H., Kodama, T., Shichiri, M., and Horiuchi, S. (1998) J. Biol. Chem.273, 28305–28313). However, a recent study also demonstrated the involvement of phosphatidylinositol 3-kinase (PI3K) in this process. In the present study, we investigated the role of PKC and PI3K in Ox-LDL-induced macrophage proliferation. Ox-LDL-induced macrophage proliferation was inhibited by 90% by a PKC inhibitor, calphostin C, and 50% by a PI3K inhibitor, wortmannin. Ox-LDL-induced expression of GM-CSF and its subsequent release were inhibited by calphostin C but not by wortmannin, whereas recombinant GM-CSF-induced macrophage proliferation was inhibited by wortmannin by 50% but not by calphostin C. Ox-LDL activated PI3K at two time points (10 min and 4 h), and the activation at the second but not first point was significantly inhibited by calphostin C and anti-GM-CSF antibody. Our results suggest that PKC plays a role upstream in the signaling pathway to GM-CSF induction, whereas PI3K is involved, at least in part, downstream in the signaling pathway after GM-CSF induction.
      Ox-LDL
      oxidized low density lipoprotein
      BSA
      bovine serum albumin
      ELISA
      enzyme-linked immunosorbent assay
      GM-CSF
      granulocyte/macrophage colony-stimulating factor
      PBS
      phosphate-buffered saline
      PI
      phosphatidylinositol
      PI3K
      phosphatidylinositol 3-kinase
      PKC
      protein kinase C
      RT
      reverse transcription
      PCR
      polymerase chain reaction
      Macrophage-derived foam cells are the key cellular elements in the early stages of atherosclerosis (
      • Ross R.
      ). Macrophages take up oxidized low density lipoprotein (Ox-LDL)1 through the scavenger receptor pathways and transform into foam cells in vitro (
      • Steinberg D.
      • Parthasarathy S.
      • Carew T.E.
      • Khoo J.C.
      • Witztum J.L.
      ). Foam cells producing various bioactive molecules, such as cytokines and growth factors, are believed to play an important role in the development and progression of atherosclerosis (
      • Ross R.
      ).
      One of the characteristic events in the atherosclerotic lesion is the proliferation of cellular components of arterial walls. In addition to the growth of vascular smooth muscle cells (
      • Ross R.
      ), several reports emphasize the presence of macrophages and macrophage-derived proliferating foam cells in the early stages of human and rabbit atherosclerotic lesions (
      • Gordon D.
      • Reidy M.A.
      • Benditt E.P.
      • Schwartz S.M.
      ,
      • Rosenfeld M.E.
      • Ross R.
      ,
      • Spagnoli L.G.
      • Orlandi A.
      • Santeusanio G.
      ). A pioneering study using starch-elicited mouse peritoneal macrophages by Yui et al.(
      • Yui S.
      • Sasaki T.
      • Miyzaki A.
      • Horiuchi S.
      • Yamazaki M.
      ) first demonstrated the Ox-LDL-induced macrophage proliferationin vitro. Subsequent studies showed the growth-stimulating capacity of Ox-LDL for other macrophages, such as mouse resident peritoneal macrophages (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sasaki T.
      • Yui S.
      • Yamazaki M.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Kodama T.
      • Suzuki H.
      • Kobori S.
      • Shichiri M.
      • Horiuchi S.
      ), rat resident peritoneal macrophages (
      • Sato Y.
      • Kobori S.
      • Sakai M.
      • Yano T.
      • Higashi T.
      • Matsumura T.
      • Morikawa W.
      • Terano T.
      • Miyazaki A.
      • Horiuchi S.
      • Shichiri M.
      ), murine bone marrow-derived macrophages (
      • Hamilton J.A.
      • Myers D.
      • Jessup W.
      • Cochrane F.
      • Byrne R.
      • Whitty G.
      • Moss S.
      ), human monocyte-derived macrophages (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sato Y.
      • Matsumura T.
      • Kobori S.
      • Shichiri M.
      • Horiuchi S.
      ), and THP-1-derived macrophages (
      • Martens J.S.
      • Reiner N.E.
      • Herrera-Velit P.
      • Steinbrecher U.P.
      ). Since macrophage-derived foam cells play an important role in the development of atherosclerotic lesions (
      • Ross R.
      ), it is possible that macrophage proliferation may modulate the progression of atherosclerosis. Thus, clarification of the mechanism of macrophage activation, proliferation, and survival process is expected to enhance our understanding of the pathogenesis of atherosclerosis. In this regard, our recent study revealed that Ox-LDL can induce a rise in intracellular calcium concentration and activate protein kinase C (PKC) in mouse peritoneal macrophages (
      • Matsumura T.
      • Sakai M.
      • Kobori S.
      • Biwa T.
      • Takemura T.
      • Matsuda H.
      • Hakamata H.
      • Horiuchi S.
      • Shichiri M.
      ). Subsequently, it was shown that activation of PKC leads to release into the culture medium of granulocyte/macrophage colony-stimulating factor (GM-CSF), which plays a priming role in the Ox-LDL-induced macrophage proliferation (
      • Biwa T.
      • Hakamata H.
      • Sakai M.
      • Miyazaki A.
      • Suzuki H.
      • Kodama T.
      • Shichiri M.
      • Horiuchi S.
      ). In a recent study using human macrophage-derived cells (THP-1 cells) and mouse peritoneal macrophages, however, Martens et al. (
      • Martens J.S.
      • Reiner N.E.
      • Herrera-Velit P.
      • Steinbrecher U.P.
      ) provided evidence that phosphatidylinositol 3-kinase (PI3K) is also involved in the Ox-LDL-induced macrophage proliferation. The present study was undertaken to determine the relationship between PI3K and PKC on one hand and induction of GM-CSF on the other, in the signaling pathway for Ox-LDL-induced macrophage proliferation.

      DISCUSSION

      Macrophages and macrophage-derived foam cells are known to proliferate in atherosclerotic lesions (
      • Gordon D.
      • Reidy M.A.
      • Benditt E.P.
      • Schwartz S.M.
      ,
      • Rosenfeld M.E.
      • Ross R.
      ,
      • Spagnoli L.G.
      • Orlandi A.
      • Santeusanio G.
      ). Recent studies showed that Ox-LDL exhibited a growth-promoting activity toward several types of macrophages in vitro (
      • Yui S.
      • Sasaki T.
      • Miyzaki A.
      • Horiuchi S.
      • Yamazaki M.
      ,
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sasaki T.
      • Yui S.
      • Yamazaki M.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Kodama T.
      • Suzuki H.
      • Kobori S.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Sato Y.
      • Kobori S.
      • Sakai M.
      • Yano T.
      • Higashi T.
      • Matsumura T.
      • Morikawa W.
      • Terano T.
      • Miyazaki A.
      • Horiuchi S.
      • Shichiri M.
      ,
      • Hamilton J.A.
      • Myers D.
      • Jessup W.
      • Cochrane F.
      • Byrne R.
      • Whitty G.
      • Moss S.
      ,
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sato Y.
      • Matsumura T.
      • Kobori S.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Martens J.S.
      • Reiner N.E.
      • Herrera-Velit P.
      • Steinbrecher U.P.
      ,
      • Matsumura T.
      • Sakai M.
      • Kobori S.
      • Biwa T.
      • Takemura T.
      • Matsuda H.
      • Hakamata H.
      • Horiuchi S.
      • Shichiri M.
      ,
      • Biwa T.
      • Hakamata H.
      • Sakai M.
      • Miyazaki A.
      • Suzuki H.
      • Kodama T.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Martens J.S.
      • Lougheed M.
      • Gomez-Munoz A.
      • Steinbrecher U.P.
      ,
      • Sakai M.
      • Shichiri M.
      • Hakamata H.
      • Horiuchi S.
      ,
      • Sakai M.
      • Biwa T.
      • Matsumura T.
      • Takemura T.
      • Matsuda H.
      • Anami Y.
      • Sasahara T.
      • Kobori S.
      • Shichiri M.
      ). However, to our knowledge, the signaling pathway(s) from binding of Ox-LDL to macrophage proliferation has not been fully defined. Since macrophage-derived foam cells are thought to play an important role in the development and progression of atherosclerotic lesions (
      • Ross R.
      ), elucidation of the mechanism of Ox-LDL-induced macrophage proliferation would be an interesting project. In this regard, we recently demonstrated that activation of PKC and subsequent release of GM-CSF play an important role in Ox-LDL-induced macrophage proliferationin vitro (
      • Matsumura T.
      • Sakai M.
      • Kobori S.
      • Biwa T.
      • Takemura T.
      • Matsuda H.
      • Hakamata H.
      • Horiuchi S.
      • Shichiri M.
      ,
      • Biwa T.
      • Hakamata H.
      • Sakai M.
      • Miyazaki A.
      • Suzuki H.
      • Kodama T.
      • Shichiri M.
      • Horiuchi S.
      ). On the other hand, Martens et al. (
      • Martens J.S.
      • Reiner N.E.
      • Herrera-Velit P.
      • Steinbrecher U.P.
      ) recently reported the involvement of PI3K in Ox-LDL-induced macrophage proliferation. Therefore, we compared in the present study the role of PKC to that of PI3K. The major conclusions of the present study could be summarized as follows. In the signaling pathway leading to macrophage proliferation, PKC is located before GM-CSF induction, whereas PI3K is located, at least in part, after GM-CSF induction (see Fig. 7). These conclusions were supported by the following findings. (i) Ox-LDL-induced macrophage proliferation was significantly inhibited by a PKC inhibitor, calphostin C, and a PI3K inhibitor, wortmannin (Fig. 1and Table I). (ii) Ox-LDL-induced GM-CSF expression and its subsequent release into the culture medium were inhibited by calphostin C but not by wortmannin (Figs. 2 and 3). (iii) In contrast, recombinant GM-CSF-induced macrophage proliferation was significantly inhibited by wortmannin but not by calphostin C (Fig. 4 and Table II). (iv) PI3K activation by Ox-LDL occurred at two time points (10 min and 4 h after the addition of Ox-LDL); the latter was inhibited by calphostin C and by an anti-GM-CSF antibody, whereas the former was not affected by an anti-GM-CSF antibody or by PKC inhibitor (Fig. 6).
      Figure thumbnail gr7
      Figure 7Schematic representation of the signaling pathways of Ox-LDL-induced macrophage proliferation. The results of the present and previous studies (Refs.
      • Matsumura T.
      • Sakai M.
      • Kobori S.
      • Biwa T.
      • Takemura T.
      • Matsuda H.
      • Hakamata H.
      • Horiuchi S.
      • Shichiri M.
      and
      • Biwa T.
      • Hakamata H.
      • Sakai M.
      • Miyazaki A.
      • Suzuki H.
      • Kodama T.
      • Shichiri M.
      • Horiuchi S.
      ) as well as those of other investigators (Refs.
      • Martens J.S.
      • Reiner N.E.
      • Herrera-Velit P.
      • Steinbrecher U.P.
      and
      • Shackelford R.E.
      • Misra U.K.
      • Florine-Casteel K.
      • Sheau-Fung T.
      • Pizzo S.V.
      • Adams D.O.
      ) support the following scheme regarding the signaling pathways of Ox-LDL-induced macrophage proliferation. Ox-LDL-induced stimulation is first transmitted into cells via an unidentified pertussis toxin sensitive G-protein (G)-coupled receptor. This activates phospholipase C (PLC), which mediates hydrolysis of phosphatidylinositol diphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). Diacylglycerol as well as calcium released from the endoplasmic reticulum (ER) stimulated by inositol triphosphate lead to activation of PKC. Activated PKC then induces the expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) and its release into the medium. Interaction of GM-CSF with its receptor leads to induction of macrophage proliferation in an autocrine or paracrine fashion either via a PI3K pathway (50%) or a PI3K-independent pathway(s) (50%). Since Ox-LDL-induced macrophage proliferation is inhibited by >80% by anti-GM-CSF antibody, the major pathway is GM-CSF-dependent (>80%), whereas the remaining portion (<20%) could be mediated by a cytokine(s) distinct from GM-CSF. Ox-LDL-induced PI3K activation at 10 min plays a minor, if any, role in Ox-LDL-induced macrophage proliferation, since it does not influence GM-CSF expression.
      Our previous results (
      • Matsumura T.
      • Sakai M.
      • Kobori S.
      • Biwa T.
      • Takemura T.
      • Matsuda H.
      • Hakamata H.
      • Horiuchi S.
      • Shichiri M.
      ,
      • Biwa T.
      • Hakamata H.
      • Sakai M.
      • Miyazaki A.
      • Suzuki H.
      • Kodama T.
      • Shichiri M.
      • Horiuchi S.
      ) and those of the present study clearly showed that the Ox-LDL-induced GM-CSF release is mediated by activation of PKC. Extensive studies using T-lymphocytes showed that GM-CSF induction following PKC activation is mainly regulated at a transcriptional level (
      • Brorson K.A.
      • Beverly B.
      • Kang S.-M.
      • Lenaldo M.
      • Schwartz R.H.
      ) and several cis-acting elements that regulate GM-CSF gene expression were identified (
      • Miyatake S.
      • Seiki M.
      • Yosida M.
      • Arai K.
      ). Moreover, T-lymphocytes were shown to express and release GM-CSF in response to PKC activators, such as phorbol 12-myristate 13-acetate and A23187 (a calcium ionophore) (
      • Gasson J.C.
      ,
      • Sugimoto K.
      • Tuboi A.
      • Miyatake S.
      • Arai K.
      • Arai N.
      ,
      • Masuda E.S.
      • Tokumitu H.
      • Tsuboi A.
      • Shilomai J.
      • Hung P.
      • Arai K.-I.
      • Arai N.
      ,
      • Wang C.-Y.
      • Bassuk A.G.
      • Boise L.H.
      • Thompson C.B.
      • Bravo R.
      • Leiden J.M.
      ). Furthermore, phorbol 12-myristate 13-acetate alone could significantly induce macrophage proliferation (
      • Matsumura T.
      • Sakai M.
      • Kobori S.
      • Biwa T.
      • Takemura T.
      • Matsuda H.
      • Hakamata H.
      • Horiuchi S.
      • Shichiri M.
      ,
      • Hamilton J.A.
      • Dientsman S.R.
      ). The PKC family is known to comprise at least 11 different isoforms of serine/threonine protein kinase, such as conventional PKC (α, β1, β2, and γ), novel PKC (δ, ε, θ, and η), and atypical PKC (ζ and λ) (
      • Hug H.
      • Sarre T.F.
      ). Activation of PKC is regulated by C1 and C2 regions (
      • Nishizuka Y.
      ). The C1 region is composed of two tandem repeats of a cysteine-rich, zinc finger-like motif, which serves as a binding site for diacylglycerol and phorbol 12-myristate 13-acetate, and the C2 region is required for calcium sensitivity (
      • Nishizuka Y.
      ). Therefore, it is possible to assume that conventional PKC containing both C1 and C2 regions is a candidate signal mediator of Ox-LDL-induced GM-CSF induction, but the involvement of novel PKC having only C1 region cannot be ruled out. With regard to downstream signaling pathways from PKC activation to GM-CSF expression, our recent study using gel shift and luciferase assays showed that a putative AP-2 binding site from −169 to −160 of the murine GM-CSF promoter was a positive responsive site and GM-κB/GC box (−95 to −73) was a negative responsive site for Ox-LDL-induced GM-CSF expression in mouse peritoneal macrophages (
      • Matsumura T.
      • Sakai M.
      • Matsuda K.
      • Furukawa N.
      • Kaneko K.
      • Shichiri M.
      ). Further studies are necessary to identify PKC isoform(s) specific for Ox-LDL-induced GM-CSF expression.
      GM-CSF is a glycoprotein-nature cytokine that regulates the differentiation, survival, and proliferation of granulocytes/macrophages (
      • Gasson J.C.
      ). The biological action of GM-CSF is mediated by its specific receptor which consists of two subunits designated α and β subunits (
      • Mitajima A.
      • Mui A.L.
      • Ogorochi T.
      • Sakamaki K.
      ,
      • Bagley C.J.
      • Woodcock J.M.
      • Hercus T.R.
      • Shannon M.F.
      • Lopez A.F.
      ). The β subunit has a long intracytoplasmic tail and plays an important role in signal transmission, but has neither an intrinsic enzyme activity nor a binding site for G proteins (
      • Rapoport A.P.
      • Abboud C.N.
      • DiPersio J.F.
      ). Binding of GM-CSF to its receptor in various types of cells generates several intracellular tyrosine phosphorylation pathways, such as Janus kinase/signal transducers and activators of transcription, Jun NH2-terminal kinase/stress-activated protein kinase, Ras-Raf mitogen-activated protein kinase, PI3K-protein kinase B, and protein kinase A (
      • Rapoport A.P.
      • Abboud C.N.
      • DiPersio J.F.
      ,
      • Miike S.
      • Hiraguri M.
      • Kurasawa K.
      • Saito Y.
      • Iwamoto I.
      ,
      • Hiraguri M.
      • Miike S.
      • Sano H.
      • Kurasawa K.
      • Saito Y.
      • Iwamoto I.
      ,
      • Hinton H.J.
      • Welham M.J.
      ,
      • Coleman D.L.
      • Liu J.
      • Bartiss A.H.
      ). In the present study, we demonstrated that Ox-LDL enhanced PI3K activity at 10 min and 4 h after the addition of Ox-LDL (Fig. 5), and that the latter was significantly inhibited by an anti-GM-CSF antibody (Fig. 6). Moreover, macrophage proliferation induced by Ox-LDL or GM-CSF was significantly inhibited by wortmannin (Tables I and II). Furthermore, an anti-GM-CSF antibody significantly inhibited Ox-LDL-induced macrophage proliferation (
      • Biwa T.
      • Hakamata H.
      • Sakai M.
      • Miyazaki A.
      • Suzuki H.
      • Kodama T.
      • Shichiri M.
      • Horiuchi S.
      ). These findings strongly suggest that activation of PI3K at the late time point is involved in Ox-LDL-induced macrophage proliferation after GM-CSF expression. However, we also demonstrated that 50 nm wortmannin produced 50% inhibition of Ox-LDL-induced macrophage proliferation (Fig. 1 and Table I). Moreover, under identical conditions, 20 μm LY294002, another PI3K inhibitor, also showed 50–55% inhibition when assessed by both thymidine incorporation and cell counting assays (data not shown). The concentrations of these PI3K inhibitors used in our experiments have been reported to be high enough to completely inhibit PI3K in human macrophages (
      • Herrera-Veit P.
      • Reiner N.E.
      ) and other types of cells (
      • Aagaard-Tillery K.M.
      ,
      • Vlahos C.J.
      • Matter W.F.
      • Hui K.Y.
      • Brown R.F.
      ,
      • Okada T.
      • Sakuma L.
      • Fukui Y.
      • Hazeki O.
      • Ui M.
      ,
      • Yao R.
      • Cooper G.M.
      ). In addition, recent reports have shown the interaction of PI3K with mitogen-activated protein kinase (
      • McLeish K.R.
      • Knall C.
      • Ward R.A.
      • Gerwins P.
      • Coxon P.Y.
      • Klein J.B.
      • Jonson G.L.
      ) or Janus kinase/signal transducers and activators of transcription (
      • Al-Shami A.
      • Naccache P.H.
      ) when cells were stimulated by GM-CSF. Thus, it is likely that the PI3K pathway is involved in GM-CSF-mediated macrophage proliferation. However, since PI3K inhibitors produce only 50% inhibition of macrophage proliferation, it is likely that another pathway is also involved, which is activated by GM-CSF but is PI3K-independent (see Fig. 7).
      Although PI3K inhibitor had no effect on Ox-LDL-mediated GM-CSF induction as well as its release into the medium (Figs. 2 and 3), it significantly inhibited Ox-LDL-induced macrophage proliferation (Figs.1 and Table I). These findings suggest that PI3K activation at 10 min after the addition of Ox-LDL may be partly responsible for macrophage proliferation. However, this pathway is GM-CSF independent. Since GM-CSF-independent pathway accounted for < 20% of macrophage proliferation, Ox-LDL-induced PI3K activation at 10 min may play a minor, if any, role in Ox-LDL-induced macrophage proliferation (Fig. 7).

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