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Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C1q-binding proteins were purified from cell surface proteins extracted from monocytes, U937 cells, or neutrophils via affinity chromatography using a matrix to which the collagen-like fragment of C1q (C1q-CLR) was immobilized (24). Proteins that bound C1q-CLR were eluted from this matrix and used as immunogens to generate mAbs that were then screened for the ability of the Ab to inhibit the C1q-induced enhancement of phagocytosis. Based on this evidence, a 126,000 Mr (reduced) protein eluted from the C1q-CLR matrix and recognized by an inhibiting mAb was then described as a receptor or receptor component for C1q. This C1q receptor, which modulates monocyte phagocytosis (C1qRP), has been purified and cloned from the U937 monocyte-like cell line (25). C1qRP is a type I membrane glycoprotein and in U937 cells is encoded by a single mRNA species of 6.7 kb. R139 and R3, the mAbs that recognize C1qRP, have been used to demonstrate surface expression of the receptor on cells of myeloid origin, such as U937 cells, monocytes, and neutrophils (26), and on human endothelial cells (27), but the receptor is not found on cells of lymphoid origin, including lymphocytes, the Raji B cell, and CEM T cell lines (26). Interestingly, the mAbs R139 and R3 inhibit the C1q-mediated enhancement of monocyte phagocytosis, but are not able to affect the superoxide production triggered by C1q in neutrophils, suggesting that the receptors that mediate these two responses differ in some way. However, since C1qRP is present on the surface of neutrophils, the possibility of this receptor playing a role in the C1q triggering of superoxide anion release cannot be completely excluded.
Two other proteins with a macromolecular structure strikingly similar to C1q are also able to mediate enhanced phagocytosis by human monocytes through C1qRP: mannose-binding lectin (MBL) and pulmonary surfactant protein A (SPA) (28, 29).5 However, unlike C1q, neither MBL nor SPA is able to trigger the neutrophil superoxide production (30). These data combined with the lack of inhibition of C1q-mediated superoxide production by the anti-C1qRP mAbs, have led us to propose that there are at least two distinct receptors on myeloid cells: C1qRP, which modulates phagocytosis, and C1qRO2, which triggers superoxide anion generation. The presence of more than one C1q receptor on the different cell types, as well as different C1q receptors on the same cell type, would be similar to that seen for IgG and C3 receptors (31, 32). To further characterize the cell type-specific expression of C1qRP and to verify that receptor expression correlates with surface mAb reactivity, molecular probes based on the recently cloned C1qRP cDNA, as well as the R139 and R3 Abs, were used to determine the expression of C1qRP in various human cell types at both the protein and mRNA level. These studies provide a critical, initial step in determining whether C1qRP, in addition to enhancing monocyte phagocytosis, participates in some of the other functions triggered by C1q.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RPMI 1640 medium, DMEM, SuperScript preamplification system for first-strand cDNA synthesis kit, TRIZOL reagent, RadPrime DNA labeling system, Taq DNA polymerase, and salmon sperm DNA were purchased from Life Technologies (Grand Island, NY). Human serum albumin, manufactured by Baxter Healthcare Corporation (Glendale, CA), was obtained from the American Red Cross Blood Services (Washington, DC). mAbs to CD19, CD3, and CD33 were purchased from Becton Dickinson (Richmond, CA). Except where noted otherwise, all other reagents were purchased in the highest quality from Sigma Chemical Co. (St. Louis, MO). Monoclonal anti-C1qRP Abs R139 (IgG2b) and R3 (IgM) and polyclonal Ab QR1 were generated as previously described (25, 26). Purified R3 IgM was obtained from ascites fluid using the ImmunoPure IgM purification kit (Pierce Chemical Co., Rockford, IL) and biotinylated using ImmunoPure NHS-LC-biotin (Pierce Chemical Co.) according to the manufacturer’s instructions. The R139 and QR1 Abs were purified by sequential octanoic acid and ammonium sulfate precipitations as described (33) and resuspended in PBS, pH 7.4.
Cells and cell culture
The U937, THP-1, and HL-60 human cell lines were obtained from the American Type Culture Collection (Rockville, MD). CEM cells were a kind gift from Dr. E. Remold-O’Donnell (Center for Blood Research, Boston, MA). U937, K562, and Raji cells were cultured in RPMI 1640 medium containing 10% supplemented bovine calf serum (HyClone Laboratories, Logan, UT). Human skin and gingival fibroblasts were biopsied from normal volunteers and, like the HeLa cell line, were cultured in DMEM supplemented with 10% FCS, 1 mM sodium pyruvate (BioWhittaker, Walkersville, MD), and 0.1 mM nonessential amino acids solution (Life Technologies). HL-60 and CEM cells were cultured in RPMI 1640 containing 20 or 10%, respectively, FCS (HyClone). THP-1 cells were grown in RPMI 1640, 10% FCS, and 5 x 10-5 M ß-mercaptoethanol. Human peripheral blood monocytes and lymphocytes were isolated by counter-flow elutriation using a modification of the technique of Lionetti et al. (34) as described (4). Blood units were collected into CPDA1 blood-pack units (Baxter Healthcare Corp., Deerfield, IL) at the UCI Medical Plaza, Irvine, CA. Cells in each preparation were checked for homogeneity according to size analysis on a Coulter Channelyzer (Miami, FL). Neutrophils were isolated from blood drawn from normal volunteers into EDTA-containing syringes. After centrifugation on lymphocyte separation medium (Organon Teknika Corp., Durham, NC) cushions and dextran sedimentation as described (15), the residual RBC were removed by hypotonic lysis.
FACS analysis
Cells were washed in HBSS containing 1 mM Ca2+, 1 mM Mg2+, 0.2% sodium azide, and 0.2% human serum albumin (FACS buffer), and subsequently incubated for 30 min on ice with mAbs R139, biotinylated R3, or isotype-matched control Abs. Cells were washed three times in FACS buffer, then incubated with either FITC-conjugated F(ab')2 anti-mouse IgG (Tago, Burlingame, CA), or PE-conjugated streptavidin (Becton Dickinson, San Jose, CA) for 30 min on ice. In some experiments, cells were then incubated with FITC-anti-CD3, PE-anti-CD19, or PE-anti-CD33 (Becton Dickinson). After washing three times in FACS buffer, the cell-associated fluorescence was measured using a FACScan or FACSCalibur (Becton Dickinson).
Northern blot analysis
HUVEC total RNA designated BC was a kind gift from Dr. Bruce Cronstein (New York University Medical Center, New York, NY). HUVEC total RNA designated JW and human iliac artery smooth muscle cell total RNA were kind gifts from Dr. Jeff Winkles (American Red Cross Holland Laboratory, Rockville, MD). Total RNA from monocytes and neutrophils was isolated using the RNA isolation kit purchased from Stratagene (La Jolla, CA). For other cell types, mRNA was isolated using the MicroFastTrack mRNA isolation kit (Invitrogen, San Diego, CA) and total RNA was isolated using TRIZOL reagent (Life Technologies) according to manufacturer’s instructions. RNA was heat denatured for 15 min at 65°C and then separated by electrophoresis through 1% agarose gels containing formaldehyde. The RNA was transferred overnight in 10x SSPE to maximum strength nytran (Schleicher & Schuell, Keene, NH) and UV cross-linked to the membrane. A C1qRP-specific probe, based on a 1458 bp cDNA insert corresponding to 74.5% of the coding region of C1qRP, was generated by the random priming method using the RadPrime DNA labeling system (Life Technologies) and 32P-labeled dCTP (DuPont-NEN Research Products, Boston, MA). A similarly generated probe specific for human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (a kind gift from Dr. Hung Fan, University of California, Irvine, CA) was used as a control for monitoring the level of RNA loaded. Hybridization of the probes were conducted for 16 to 20 h at 42°C in 50% formamide, 5x SSPE, 5x Denhardt’s reagent, 0.1% SDS, and 0.1 mg/ml salmon sperm DNA. After washing twice in 6x SSPE, 0.1% SDS for 15 min each at room temperature, twice in 1x SSPE, 0.1% SDS for 15 min at 37°C, and once in 1x SSPE, 0.1% SDS for 30 min at 60°C, bound probes were detected by autoradiography.
RT-PCR analysis for C1qRP expression
Total RNA isolated as described above was treated with RQ1 RNase-free DNase (Promega, Madison, WI) according to the manufacturer’s instructions. First-strand cDNA synthesis from 2 µg of total RNA was conducted using the SuperScript preamplification system (Life Technologies) with random hexamers as primers. As a control for the presence of residual genomic DNA in the RNA preparations, parallel cDNA synthesis reactions were conducted in the absence of the reverse transcriptase. Two microliters of the 20-µl cDNA synthesis reaction were used in 50-µl PCR reactions containing 20 mM Tris-HCl (pH 8.4), 50 mM KCl, 1.5 mM MgCl2, 0.2 mM of each dNTP, 0.1 µM of each primer, and 2 U of Taq DNA polymerase (Life Technologies). The C1qRP primers that amplify a 538-bp cDNA are 5'-AGCTGAGCGCTGCCGAGGCCCA-3' for the sense primer and 5'-TTGGCCGCAGAGGCAAAGGGCA-3' for the antisense primer. RT-PCR control amplimer sets for human ß-actin and transferrin receptor were purchased from Clontech (Palo Alto, CA). After an initial 2-min denaturing at 94°C, PCR amplification was conducted for 30 cycles of denaturing for 30 s at 94°C, annealing for 30 s at 60°C, and extension for 1 min at 72°C in a Perkin-Elmer DNA thermal cycler (Norwalk, CT). PCR products were resolved on 1% agarose gels run in TAE according to standard protocols (35) and stained with ethidium bromide.
Platelet C1qRP Immunoprecipitation
Normal human platelet lysate (in 20 mM Tris-HCl, pH 8, 0.1 M NaCl, 1% Triton X-100, 10 mM N-ethylmaleimide, 0.01% leupeptin) was kindly provided by Dr. Diane Nugent of Children’s Hospital of Orange County, Orange, CA. The total protein concentration of the lysate was 8.25 mg/ml. The immunoprecipitation was performed as described (26) using 333 µl of the platelet lysate or 8.3 x 106 cell equivalents of freshly elutriated (4) human monocytes (in the above lysis buffer) per sample. Precipitated material was separated by SDS-PAGE, transferred to nitrocellulose (Schleicher & Schuell) as described (25), and probed with the biotinylated R3 mAb. Bound Ab was detected chemiluminescently with streptavidin-horseradish peroxidase and the HRPL Western kit (National Diagnostics, Atlanta, GA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mAbs R139 (IgG2b) and R3 (IgM) recognize the
extracellular domain of C1qRP, which was previously shown
to be expressed on human monocytes, neutrophils, the U937 monocyte-like
cell line, and endothelial cells (26, 27), but not on lymphocytes or
the Raji and CEM lymphoblastoid cell lines (26). To further examine the
cell surface expression of C1qRP on other cell types, the
two mAb were used in FACS analysis of various primary and established
cell lines. Of the cells examined in this study, the acute monocytic
leukemia cell line THP-1 and the chronic myelogenous leukemia cell line
K562 were found to express C1qRP, at substantially lower
levels, however, compared with U937 cells (Fig. 1
). The epithelial-like HeLa cell line
was not reactive with either of the anti-C1qRP mAbs.
Human fibroblasts have been reported to bind and respond functionally
to C1q (21, 22, 36, 37); however, neither human skin or gingival
fibroblasts express C1qRP as determined by R139 and R3
reactivity (Fig. 1).
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,25-dihydroxy-vitamin D3 and PMA)
and granulocytic differentiation (with DMSO and retinoic acid) over a
6-day period. FACS analysis of the differentiated cells showed no
increase in R139 and R3 reactivity over untreated HL-60 cells (data not
shown). Differentiation was verified by the changes in morphology and
adherence of the cells, by the expected increases in CD14 expression
for monocytic differentiation (39), and in CR3 expression for
granulocytic and monocytic differentiation (40), as determined by FACS
analysis and by an increase in phorbol 12,13-dibutyrate-induced
superoxide production by DMSO and retinoic acid differentiated
cells. Northern blot analysis
Because the mAbs are specific for distinct epitopes on the
receptor protein, it is possible that C1qRP may be
present on different cell lines but that the mAb-binding epitopes may
be missing, altered, or in a different conformation, such that they are
no longer accessible to the Abs. Therefore, RNA isolated from the
different cell types was subjected to Northern blot analysis using a
1458-bp cDNA fragment corresponding to approximately 75% of the
receptor’s coding region to test for the presence of C1qRP
RNA. C1qRP mRNA from U937 cells migrates as a single
species of 6.7 kb in denaturing agarose gels (25) and is easily
detected (Fig. 2). The single 6.7-kb RNA
transcript was found in all cell types in which receptor expression was
detected by the mAbs, including U937 cells, monocytes, endothelial
cells, THP-1 cells, and neutrophils (Fig. 2, A and
B). Receptor RNA was detected, albeit at very low
levels, in mRNA isolated from K562 cells (Fig. 2A),
consistent with the level of protein expression detected by the
anti-C1qRP Abs. Conversely, C1qRP
expression was not detected in mRNA isolated from skin or gingival
fibroblasts, HeLa, Raji, or CEM cells (Fig. 2A),
consistent with the lack of detectable surface immunoreactivity with
R139 and R3 (Fig. 1
and 26 . In total RNA isolated from elutriated
lymphocytes, HL-60 cells, and iliac artery smooth muscle cells, C1q
receptor expression was also not detected (Fig. 2B).
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To verify the results of the Northern blot analysis, RT-PCR, a
more sensitive method for the detection of C1qRP RNA
transcripts in the various cells, was employed. Total RNA was isolated
from the cells and used to generate cDNA using random hexamers as
primers. The resulting cDNA was then used as the template in PCR
reactions to amplify a 538-bp fragment of C1qRP that
corresponds to 27.5% of the protein coding region. As shown in Figure 3, U937 cells, monocytes, neutrophils,
THP-1, and endothelial cells express the receptor. Again, K562 cells
express a lower level of the receptor RNA. Consistent with the pattern
of receptor expression determined by the other methods, HL-60, HeLa,
Raji, CEM, and both skin and gingival fibroblast RNA do not contain a
detectable amount of C1qRP transcripts. While
C1qRP mRNA was not detected in these cell lines, either the
ß-actin gene or the transferrin receptor gene, each of which is
expressed at low levels in these cells, was detected, verifying the
presence of RNA from the different cell types in the RT-PCR reactions.
In all cases, control reactions in the absence of reverse transcriptase
to check for genomic DNA contamination were negative (data not
shown).
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B), and FACS analysis of the
lymphocyte population stained with the R139 mAb are distinctly
negative, cells stained with the R3 mAb occasionally demonstrate a very
slight increase in their mean fluorescence intensity vs control cells
(26). While the population did not contain any monocytes as determined
by size analysis on a Coulter Channelyzer (data not shown), it is
possible that the isolated population does contain a small number of
myeloid progenitor cells, such as peripheral blood dendritic cells
(41), that express C1qRP, even in an undifferentiated
state, similar to U937 and K562 cells. Cells of myeloid lineage have
the cell surface marker CD33, which distinguishes these cells from
other blood leukocytes. However, FACS analysis of elutriated
lymphocytes stained with an anti-CD33 Ab did not detect a positive
population of myeloid cells (data not shown). Additional FACS analyses
demonstrate that the elutriated lymphocyte population contained neither
CD3+ T cells nor CD19+ B cells, which also
stained positive with the anti-C1qRP Abs (data not
shown), and thus the source of the RT-PCR signal remains unknown. Human platelets express C1qRP
The reported C1q-mediated effects on human platelets include
inhibition of the collagen-induced platelet aggregation (10, 42, 43)
and induction of IIb/ß3 integrins,
expression of P-selectin, and procoagulant activity (44). These
functional observations, along with the demonstration that free C1q
binds specifically to human platelets (10), suggest that surface C1q
receptors exist on these cells. To determine whether C1qRP
could have a role in platelet function in response to C1q, detergent
extracts of isolated human platelets were subjected to
immunoprecipitation and detection with the anti-C1qRP
mAbs. As shown in Figure 4, a 100,000
Mr (nonreduced) band similar in size to
C1qRP precipitated from U937 detergent extracts is detected
in the platelet lysate. Additionally, this platelet molecule reacts
with both the R139 and R3 mAbs, indicating that platelets do in fact
express C1qRP.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and 3). However, C1q can still bind (11) and trigger
superoxide release from these cells (45), consistent with the
hypothesis that the receptors modulating C1q-mediated superoxide
generation and enhanced phagocytosis are distinct. The promyelocytic cell line HL-60, in which C1qRP was not detected at either the protein or RNA level, is one exception in the pattern of C1qRP expression in cells of myeloid lineage. These cells consist primarily of neutrophilic promyelocytes. Thus, since blood neutrophils that express C1qRP are terminally differentiated, the HL-60 cells may not be at a differentiation state in which the receptor is expressed. Thus far, our studies using various chemical agents to induce differentiation of these cells have not resulted in C1qRP expression. We conclude that additional factors or differentiation parameters must be present to induce C1qRP expression in the HL-60 cell line.
The pattern of expression of C1qRP reported here sharply distinguishes this receptor from two other reported C1q-binding proteins, which have been termed cC1qR and gC1qR. Ghebrehiwet and colleagues, and later others, isolated a 60,000 Mr protein termed cC1qR, since it was originally characterized as binding to the collagen-like region of C1q. More recent reports suggest that it may be identical to calreticulin (46), a Ca2+-binding protein found in several cellular compartments, with many postulated functions (47, 48). In contrast to the restricted expression of C1qRP, the 60,000 Mr protein is present on human B cells, Raji cells, and human T cells (49, 50, 51, 52) as well as on most other cell types tested (11, 53, 54, 55, 56). There is some in vitro evidence that cC1qR is involved in C1q-induced platelet aggregation (reviewed in 57 . However, a C1q response mediated by this 60,000 Mr protein has yet to be demonstrated on myeloid or endothelial cells.
gC1qR is another protein identified as binding the globular heads of C1q (58). While originally reported to be a 33-kDa glycoprotein expressed on the surfaces of vascular and blood cells (58, 59, 60), the apparent lack of a transmembrane domain or a consensus sequence for glycosylphosphatidylinositol anchoring does not make it obvious how gC1qR attaches to the membrane for the reported surface detection of this protein. Recent studies by van den Berg and coworkers and Muller-Esterl and colleagues demonstrate that gC1qR is not detected significantly on the surfaces of most of these cells by FACS analysis (61, 62). Rather, they propose that this 33-kDa protein is a soluble, intracellular or vesicular protein that can be secreted, but not as cell surface receptor. Additionally, Herwald and coworkers and Lim et al. have demonstrated kininogen-binding (63) and vitronectin-binding (64) activities for this 33-kDa protein independent of C1q. A cellular response to C1q mediated by gC1qR has not yet been demonstrated.
The relatively high levels of expression of C1qRP on endothelial cells is quite interesting in that C1q has been shown to bind to endothelial cells in a receptor-mediated fashion (7, 8) and has been shown to mediate binding of immune complexes and aggregates to endothelial cells in vitro (9). In addition, C1q bound to immune complexes induces an increase in the adhesive properties of endothelial cells for leukocytes (27) and, alone, mediates the binding of the S. minnesota Re mutant to pulmonary endothelial cells and elevates the level of superoxide anion release from these cells in response to the bacteria (20). While both the 60,000 Mr cC1qR- and 33,000 Mr gC1qR-binding proteins have been shown to be expressed by endothelial cells (27, 55, 62), thus far, the only function demonstrated by either cC1qR or gC1qR derived from endothelial cells is the inhibition of complement-mediated lysis of C1q-sensitized erythrocytes by cC1qR (65, 66). Whether or not C1qRP, cC1qR, or gC1qR is involved in the C1q-mediated increase in endothelial cell adhesiveness for leukocytes, or the binding and destruction of bacteria by endothelial cells triggered by C1q, remains to be investigated.
The ability to selectively enhance a defense mechanism such as
phagocytosis with limited, if any, additional effects on other systemic
functions in immunocompromised patients, including those with AIDS,
individuals with genetic immunodeficiencies, or patients undergoing
surgery with high risk of infection, may provide a highly effective
means of promoting positive clinical outcomes for these patients. In
addition to C1q, MBL, and SPA, other agents such as cytokines (67, 68)
and specific extracellular matrix proteins (69) have also been shown to
enhance phagocyte function. However, some of these cytokines, such as
TNF- and granulocyte-macrophage CSF, also trigger massive superoxide
anion release from neutrophils directly, which would have devastating
effects on host tissues (70). Additionally, TNF- has been shown to
activate integrated HIV-1 and cause enhanced virus production (71). In
contrast, recent studies by Jasinskiene and
coworkers6 demonstrate that
C1q and SPA do not trigger the release of proinflammatory cytokines by
human monocytes. Similarly, Wright and colleagues demonstrated that SPA
limits the proinflammatory response of macrophages (72). Thus, since
C1qRP appears to be limited in both cellular expression and
function (phagocytosis), it may be possible to specifically modulate
this receptor to enhance the phagocytic response without generating
unwanted, deleterious side effects including, but not limited to,
induction of virus expression caused by cytokines.
In summary, the data provided here help delineate the specific receptor interactions possibly involved in mediating particular C1q-induced functions. Subsequent identification of critical ligand-receptor interaction sites should facilitate the design of selective modulators of desired responses (enhanced phagocytic capacity via C1qRP) without the induction of proinflammatory cytokines or generation of toxic superoxide anions.
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Acknowledgments |
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Footnotes |
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2 Current address: Stanford University School of Medicine, MSLS, 3rd Floor, MC:5487, Stanford, CA 94305.
3 Address correspondence and reprint requests to Dr. Andrea J. Tenner, Department of Molecular Biology and Biochemistry, University of California-Irvine, 3205 Biological Sciences II, Irvine, CA 92697. E-mail address:
4 Abbreviations used in this paper: CCP, classical complement pathway; CR, complement receptor; MBL, mannose binding lectin; SPA, pulmonary surfactant protein A; C1q-CLR, collagen-like fragment of C1q; PE, phycoerythrin; SSPE, standard saline-phosphate-EDTA; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
5 R. R. Nepomuceno, S. Ruiz, M. Park, and A. J. Tenner. C1qRP is a heavily O-glycosylated cell surface protein involved in the regulation of phagocytic activity. Manuscript in preparation.
6 N. Jasinskiene, R. Rochford, S. Ruiz, and A. J. Tenner. Complement component C1q selectively enhances phagocytosis but not the production of proinflammatory cytokines. Manuscript in preparation.
Received for publication September 9, 1997. Accepted for publication October 30, 1997.
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R. R. Nepomuceno, S. Ruiz, M. Park, and A. J. Tenner C1qRP Is a Heavily O-Glycosylated Cell Surface Protein Involved in the Regulation of Phagocytic Activity J. Immunol., March 15, 1999; 162(6): 3583 - 3589. [Abstract] [Full Text] [PDF]
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