Published online before print April 9, 2004
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R triggers shedding of the hemoglobin-haptoglobin scavenger receptor CD163
Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire
1Correspondence at current address: Harvard School of Public Health, Department of Environmental Health, Physiology Program, 665 Huntington Ave., Building I, 13th Floor, Boston, MA 02115. E-mail: tsulahia{at}hsph.harvard.edu
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(TNF-), surface CD163 is proteolytically cleaved from the plasma membrane in response to lipopolysaccharide (LPS) stimulation. As cross-linking of the Fc
receptor (FcR) is similarly known to induce TNF- shedding, the effect of FcR stimulation on CD163 shedding was investigated. We found that FcR stimulation resulted in a rapid release of surface CD163 into the supernatant that was blocked by inhibitors of protein kinase C and tyrosine kinases. Although LPS and FcR stimulation in short-term cultures suppressed CD163 mRNA expression, long-term cultures of monocytes treated with LPS—but not with a FcR cross-linking reagent—resulted in an interleukin-10-dependent recovery of surface CD163 expression. These studies suggest that the presence of immune complexes in infection or autoimmunity may radically alter the nature of CD163-dependent monocyte/macrophage processes. This may be particularly important in disease states in which immune complexes and high levels of free Hb are present, such as in autoimmune hemolytic anemia, transfusion reactions, or infections by hemolytic bacteria.
Key Words: lipopolysaccharide • protein kinase C • SRCR family • monocyte • tyrosine kinases
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and tumor necrosis factor (TNF-) decrease CD163 expression [8
9
10
]. Moreover, CD163-bright macrophages often accumulate at sites of chronic inflammation [9
, 11
12
13
14
]. Collectively, these findings imply a functional role for CD163 in the resolution of inflammation.
Although much research has focused on the function and regulation of surface-expressed CD163, a truncated, soluble form has been described that appears to be derived by active shedding of CD163 from the cell surface. Initially, phorbol 12-myristate 13-acetate (PMA) was shown to induce proteolytic cleavage of surface CD163 [15
]. More recently, soluble CD163 (sCD163) was identified as a component of normal human plasma [16
]. Furthermore, Hintz et al. [17
] used a natural stimulus of monocyte activation, lipopolysaccharide (LPS), to trigger CD163 shedding in vivo and in vitro. This study demonstrated that the metalloproteinase class of enzymes mediated shedding, as TNF- protease inhibitor-0 (TAPI-0) was capable of blocking LPS-induced shedding. TAPI-0 is an inhibitor of TNF--converting enzyme (TACE) and can protect mice from a lethal dose of LPS by inhibiting the release of TNF- in vivo [18
, 19
]. As such, TACE has been suggested as a possible candidate for the enzyme responsible for CD163 shedding [17
].
In addition to LPS stimulation, Fc receptor (FcR) cross-linking has been shown to stimulate TNF- release from monocytes [20
]. FcRs are expressed on a number of leukocytes and are important in bridging the innate and acquired immune systems. They do this by binding the Fc region of antibodies (Ab) of the immunoglobulin G (IgG) isotype, which simultaneously bind via their F(ab')2 region to particles such as viruses, bacteria, and foreign cells. This results in the cross-linking of FcRs, eliciting responses that include phagocytosis, antigen-dependent cellular cytotoxicity, and inflammatory cytokine release [21
]. LPS stimulates macrophage secretion of TNF- and other proinflammatory cytokines predominantly by activating the nuclear factor-
B pathway via Toll-like receptor 4 (reviewed in ref. [22
]). Thus, FcR and LPS signaling pathways mediate monocyte macrophage activation in response to bacterial infection and stimulate inflammatory reactions. Notably, the signaling cascades initiated by LPS or FcRs intersect in a number of places, including protein kinase C (PKC), Src kinases, and phosphatidylinositol-3 kinase [22
, 23
]. In addition, FcR and LPS trigger TNF- release by the same class of proteases that appear to be responsible for CD163 shedding. These data led us to hypothesize that FcR stimulation would also trigger CD163 shedding. In this report, we demonstrate that FcR cross-linking induces rapid cleavage of surface CD163, which is PKC- and tyrosine kinase-dependent. In addition, long-term stimulation by LPS, but not by FcR, up-regulates CD163 surface expression in an IL-10-dependent manner.
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Shedding of CD163
Opsonized sheep red blood cells (op-SRBC) were generated as described previously [25
]. Briefly, SRBC (Quad Five, Ryegate, MT) were washed with phosphate-buffered saline (PBS) and were incubated with a nonagglutinating titer (1:5000) of rabbit anti-SRBC IgG (Rockland Immunochemicals, Gilbertsville, PA) in Hepes-buffered RPMI 1640/gentamicin/10% HI FBS. This incubation was conducted for 30 min at room temperature. The op-SRBC were then washed with Hepes-buffered RPMI 1640/gentamicin/10% HI FBS. Cell culture substrate coated with immobilized IgG (iIgG) was generated by incubating a 96-well plate overnight at 37°C with 200 µg/ml intravenous immunoglobulin (IVIg; Alpha Therapeutic Corp., Los Angeles, CA) in PBS. The plate was then washed extensively with PBS to remove any unbound IVIg. Rabbit anti-SRBC IgG, SRBC, and IVIg were tested for LPS contamination by the Limulus amebocyte lysate assay (QCL-1000, BioWhittaker, Walkersville, MD) as per the manufacturer’s instructions. In some experiments, rabbit anti-SRBC IgG, IVIg, and LPS were boiled for 4 min before being used to opsonize SRBC, coat plates, or stimulate cells, respectively.
In other experiments, 96-well plates were incubated overnight at 37°C with 100 µl of 2 µg/ml F(ab')2 goat anti-mouse Fc Ab (Jackson Immunoresearch, West Grove, PA). The plates were then washed and blocked with 200 of µl 2 mg/ml bovine serum albumin (Sigma Chemical Co., St. Louis, MO) for 30 min at 37°C. After further washing, 100 of µl 2 µg/ml monoclonal Ab (mAb) clones 32 (anti-FcRI, Medarex, Princeton, NJ), AT10 (anti-FcRII, generously given by Dr. Martin Glennie, University of Southhampton), 3G8 (FcRIII, Medarex), a combination of all three, or an equivalent concentration of an isotype control were added and incubated at 37°C for 1 h. Unbound mAb were washed away before mononuclear cells were added, incubated, and analyzed for CD163 surface levels as described below. Freshly isolated or cultured PBMCs were plated at a concentration of 5 x 105 cells per well into wells that contained immobilized anti-FcR mAb, iIgG, 3 x 105 op-SRBC, or 10 ng/ml LPS (Sigma Chemical Co.). PBMCs were cultured with these stimuli for 3 h, unless otherwise indicated. After 3 h, the culture supernatant was harvested and analyzed for sCD163, and the monocytes were analyzed for CD163 surface expression. In some experiments, cells were cultured for up to 3 days in the presence of iIgG or LPS and 0.5 µg/ml of a neutralizing anti-IL-10 mAb or an isotype control (BD PharMingen, San Diego, CA).
Protein kinase inhibitors
Where indicated, pharmacological inhibitors were used during CD163 shedding. Bisindolylmaleimide I (BIM I, a PKC inhibitor) and genistein (a protein tyrosine kinase (PTK) inhibitor) were purchased from Calbiochem (La Jolla, CA). PBMCs were preincubated for 1 h with 10 µM BIM I, 100 µM genistein, or vehicle (0.4% dimethyl sulfoxide (DMSO)) before shedding stimuli were applied. The BIM I and genistein stocks were tested for LPS contamination using the Limulus assay.
CD163 measurement
Following culture of PBMC with shedding stimuli, cell-free culture supernatants were harvested, diluted 1:2, and stored at –80°C until analysis. sCD163 levels were measured using a previously described enzyme-linked immunosorbant assay (ELISA) [16
], with slight modification. ELISA plates were coated overnight with 2 µg/ml of the CD163-specific mAb, Mac 2-158 (Maine Biotechnology Services, Portland). The plates were washed and then blocked for 30 min with PBS/10% FBS. After coating and washing, supernatant or a sCD163 standard plasma sample (kindly provided by K. A. Goldstein, Dartmouth Medical School; ref. [17
]) was added and incubated for 1 h. The plates were then washed, and 0.5 µg/ml biotinylated RM3/1 (anti-CD163, Bachem, King of Prussia, PA) was added. After incubating for 1 h, the plates were washed again, and avidin–horseradish peroxidase (1:1000, Sigma Chemical Co.) was added. The plates were incubated for 30 min, washed, and then developed using the TMB Microwell peroxidase substrate system (Kirkegaard and Perry Laboratories, Gaithersburg, MD) according to the manufacturer’s instructions. Surface CD163 was analyzed by flow cytometry as described previously [7
], except that Mac 2-158 was used in place of Mac 2-48. Briefly, PBMCs were chilled on ice and washed three times. Human IgG (Sigma Chemical Co.) was added at a final concentration of 4 mg/ml to block FcRs, and the cells were stained with 20 µg/ml Mac 2-158 or an isotype control for 1 h. Following this incubation, cells were washed and stained with 17.5 µg/ml fluorescein isothiocyanate-labeled goat F(ab')2 anti-mouse Ig (Caltag Laboratories, Burlingame, CA) for 1 h, then washed, and fixed with PBS/1% methanol-free formalin until analysis. Fluorescence of monocytes (gated using forward- and side-scatter; ref. [26
]) was analyzed using a Becton Dickenson FACScan (San Jose, CA). Mean fluorescence intensity (MFI) was calculated by subtracting the MFI of the isotype control-stained monocytes from the MFI of the corresponding Mac 2-158-stained monocytes.
Isolation of RNA and real-time polymerase chain reaction (PCR)
Monocytes were isolated from leukapheresis packs by cold aggregation as described previously [27
]. Four million monocytes per well were cultured for 18 h in 1.5 ml RPMI/gentamicin/10% HI FBS in the presence of iIgG, 10 ng/ml IL-10, or 10 ng/ml LPS. After stimulation, monocytes were harvested, and total cellular RNA was extracted using the RNeasy mini kit (Qiagen, Valencia, CA) as per the manufacturer’s instructions. To eliminate genomic DNA contamination, all RNA samples were treated with RNase-free DNase 1 (Qiagen), and RNA purity was verified by formaldehyde/agarose gel electrophoresis.
First-strand cDNA was synthesized with oligo (d)T12–18 template primer and SuperScript II Moloney murine leukemia virus–reverse transcriptase kit (Invitrogen, Carlsbad, CA). cDNA (12 ng per well) was transferred into iCycler 96-well plates (Bio-Rad, Hercules, CA), and SYBR Green PCR master mix (Applied Biosystems, Foster City, CA) was added in accordance with the manufacturer’s instructions. The primer pairs used for amplification of CD163 were (5'-3'): CGA GTT AAC GCC AGT AAG G and GAA CAT GTC ACG CCA GC, and those for ß-actin were (5'-3'): CCT ATG TGG GCG ACG AG and GCG CAG CTC ATT GTA GAA G. Amplification was performed on an iCycler with an optical unit (Bio-Rad). The thermal profile for SYBR PCR consisted of 5 s initial denaturation at 95°C followed by 40 cycles of 15 s at 95°C, 45 s at 63°C, and 15 s at 72°C. Amplicon accumulation was measured during the extension phase. Data were analyzed using the iCycler analysis software, version 2.3 (Bio-Rad), and melting curve analysis was performed to ensure the specificity of each amplification.
Statistical analysis
For experiments addressing the effect of the blocking anti-IL-10 mAb, the Welch’s modified t-test was used to test for significant differences between the means. For other experiments, an ANOVA and Dunnett’s multiple comparison test were used. Statistical analysis was performed using Instat 2.03 for the Macintosh (Graphpad Software, San Diego, CA).
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R stimulation trigger CD163 sheddingRs can also trigger shedding. To address this question, fresh PBMCs were isolated and stimulated for 3 h with LPS, iIgG, or op-SRBC. The supernatants were harvested and tested for sCD163 expression, and the cells were stained for surface CD163. As shown in Figures 1
and 2
, stimulation of cells via FcRs, like LPS, resulted in significant shedding of CD163 from the cell surface into the supernatant. This was true whether the cells were stimulated with plate-bound IgG (iIgG) or with an opsonized particle (op-SRBC). In addition, if the human IgG or rabbit anti-SRBC IgG were boiled before use, shedding was completely abolished. In contrast to the Abs, boiling LPS did not inhibit shedding. This demonstrates that CD163 shedding mediated by iIgG or op-SRBC is not an artifact of LPS contamination and that the op-SRBC-induced shedding is not a result of the SRBC itself but rather due to the IgG bound to its surface.
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Figure 1. FcR cross-linking causes CD163 shedding from the monocyte surface. Freshly isolated (A) or DEX- and IL-10 treated (B) PBMCs were incubated in the presence or absence of iIgG for 3 h and were stained for surface CD163 expression. Heavy lines represent surface CD163 levels on control monocytes. Solid lines signify CD163 levels on iIgG-treated monocytes. Dotted lines represent the fluorescence of monocytes stained with an isotype control. Data are representative of four donors.
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Figure 2. CD163 shedding by freshly isolated monocytes. PBMCs were incubated with boiled or unboiled LPS, iIgG, or op-SRBC for 3 h. Cells were then stained for surface CD163 expression (A), and the culture supernatants were analyzed for sCD163 (B). Data presented are representative of four donors. Error bars represent the standard deviation of triplicate measurements. *, Mean significantly different from control (P<0.01).
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R cross-linking could induce CD163 shedding from GC- and IL-10-pretreated monocytes, which express CD163 at extremely high levels [7
]. PBMCs were cultured overnight in the presence of IL-10 and DEX to up-regulate CD163 expression before FcR cross-linking or LPS treatment. As with freshly isolated cells, the DEX- and IL-10-treated monocytes shed CD163 in response to LPS and FcR stimulation (Figs. 1
and 3
).
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Figure 3. CD163 shedding by DEX and IL-10-treated monocytes. PBMCs were treated with DEX and IL-10 overnight and were then incubated with boiled or unboiled LPS, iIgG, or op-SRBC for 3 h. Cells were then stained for surface CD163 expression (A), and the culture supernatants were analyzed for sCD163 (B). Data presented are representative of four donors. Error bars represent the standard deviation of triplicate measurements. *, Mean significantly different from control (P<0.01).
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R-mediated CD163 shedding directly and to determine which FcRs are responsible for this, mAb specific for distinct FcRs were used. As illustrated in Figure 4
, cross-linking individual FcR subtypes caused a significant decrease in surface CD163 levels. Although each FcR was capable of triggering CD163 shedding, FcRI and FcRII were more effective than FcRIII. Furthermore, cross-linking FcRI or FcRII alone resulted in surface CD163 levels that were similar to those following cross-linking of all three FcRs in concert. Taken together, these data suggest that the individual FcRs play redundant roles in the shedding of CD163 and that (at least in the case of FcRI and FcRII) cross-linking a single receptor subtype is sufficient for maximal CD163 shedding.
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Figure 4. CD163 shedding by FcR-specific mAb. PBMCs were incubated for 3 h with immobilized anti-FcRI (32), anti-FcRII (AT10), anti-FcRIII (3G8), a combination of all three, or an isotype control. Cells were then stained for surface CD163 expression. Data presented are representative of three donors. Error bars represent the standard deviation of triplicate measurements. *, Mean significantly different from the isotype control (P<0.01). MFI values for isotype control-treated cells were comparable with those of untreated cells (data not shown).
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R signaling [21
], the effect of the PTK inhibitor genistein on CD163 shedding was examined. As shown in Figure 5
, treatment of cells with genistein completely inhibited FcR-induced CD163 shedding, but had no effect on shedding caused by LPS stimulation. Therefore, phosphorylation of tyrosine residues is critical for FcR- but not LPS-triggered shedding. This is in contrast to LPS regulation of TNF- production, in which treatment of macrophages with genistein markedly attenuates TNF- protein and mRNA production [28
].
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Figure 5. Inhibition of CD163 shedding by kinase inhibitors. PBMCs were incubated with iIgG or LPS in the presence of BIM I, genistein, or vehicle (DMSO) for 3 h. Cells were then stained for surface CD163 expression (A), and the culture supernatants were analyzed for sCD163 (B). Data presented are representative of three donors. Error bars represent the standard deviation of triplicate measurements. *, Mean significantly different from the DMSO condition for that particular shedding stimulus (P<0.01).
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R signaling pathways [22
, 23
]. Therefore, the PKC inhibitor BIM I was used to test whether PKC activation plays a role in LPS- or FcR-stimulated shedding. In contrast to genistein, BIM I dramatically inhibited CD163 shedding elicited by FcR or LPS, suggesting that these stimuli share at least one common, PKC-dependent pathway.
FcR stimulation decreases CD163 mRNA levels
As previous data established that LPS suppresses CD163 mRNA expression [10
], the effect of FcR ligation on CD163 mRNA levels was investigated. Purified monocytes were cultured for 18 h in the presence of IL-10, LPS, or iIgG. Relative CD163 mRNA expression was then analyzed by real-time PCR (Fig. 6
). For all donors, treatment with IL-10 more than doubled the levels of CD163 mRNA. In contrast, LPS and FcR stimulation resulted in up to three- and 12-fold reductions in the levels of CD163 mRNA, respectively. When given in conjunction with IL-10 treatment, FcR stimulation completely inhibited the CD163 mRNA increase, resulting in CD163 mRNA levels that were below control values.
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Figure 6. Suppression of CD163 mRNA by FcR stimulation. Purified monocytes were incubated for 18 h with the indicated stimuli in the presence or absence of iIgG. Cells were then harvested, and relative CD163 mRNA levels were measured by real-time PCR. Data points indicate the mean of duplicate mRNA measurements from each donor.
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R stimulation, PBMCs were cultured in the presence of LPS, iIgG, or op-SRBC for various periods of time before being stained for CD163 expression (Fig. 7
). As previously reported [17
], LPS induced a rapid shedding of CD163. Considerable shedding was detected by 1 h of culture and was maximal by 3 h. Shedding induced by op-SRBC demonstrated nearly identical kinetics, except that surface CD163 levels continued to drop after 3 h and reached their lowest levels after 1 day. Cells stimulated with iIgG showed a slight lag in their shedding kinetics, demonstrating minimal shedding at 1 h. However, by 3 h, the surface CD163 levels of iIgG-stimulated cells were comparable with those of LPS- and op-SRBC-stimulated cells.
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Figure 7. Time-course of CD163 shedding and recovery. Two representatives (A and B) of three donors are presented. PBMCs were incubated with iIgG, op-SRBC, or LPS for varying times. Cells were then stained for CD163 surface expression. Error bars represent the standard deviation of triplicate measurements.
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R-induced shedding did not result in a dramatic rebound in surface CD163 at the 3-day time-point. In fact, these levels were consistently lower than those of cells that had received no stimulus for 3 days. These data indicate that although LPS and FcR stimulation result in short-term shedding of CD163, the long-term consequences of these two stimuli are quite different. As LPS treatment results in monocyte production of IL-10 [29 ], which in turn increases CD163 levels [7 , 10 ], we hypothesized that IL-10 may play a role in the LPS-mediated CD163 superinduction observed in Figure 7 . To test this, PBMCs were cultured for 3 days in the presence of LPS, iIgG, and a neutralizing anti-IL-10 mAb or an isotype control. As shown in Figure 8 , the neutralizing mAb had no effect on control or iIgG-treated cells. However, it completely inhibited CD163 recovery by LPS-treated cells. These data indicate that IL-10 is required for the recovery and superinduction of CD163 during prolonged LPS exposure. This is further supported by identical experiments in which LPS treatment consistently induced high levels of IL-10 (>800 pg/ml), and iIgG treatment resulted in low levels of IL-10 (<15 pg/ml; data not shown).
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Figure 8. CD163 shedding and recovery by freshly isolated monocytes. PBMCs were incubated with LPS or iIgG for 3 days in the presence of a neutralizing anti-IL-10 mAb or isotype control. Cells were then stained for surface CD163 expression. One representative of three donors is presented. Error bars represent the standard deviation of triplicate measurements. *, Mean significantly different from the isotype control for that particular shedding stimulus (P<0.01).
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R cross-linking on monocyte CD163 expression had not yet been investigated. As LPS has been shown to induce metalloproteinase-mediated shedding of CD163 and TNF- [17
, 30
31
32
], and FcR signaling has also been shown to trigger the release of soluble TNF- [20
], we hypothesized that FcR, like LPS, would elicit the shedding of CD163. In this report, we demonstrate that stimulation by LPS or FcR results in a dramatic loss of CD163 from the surface of the cell and a concomitant increase of sCD163 in the supernatant of freshly isolated and DEX- and IL-10-treated monocytes. This suggests that FcR cross-linking signals a proteolytic shedding of CD163, regardless of the monocyte activation status, as has been described for LPS [17
]. Furthermore, FcR-mediated shedding (like LPS) is partially inhibited by the metalloprotease inhibitor TAPI-0 (data not shown). This suggests that FcR cross-linking and LPS stimulation may result in the activation of a similar protease or group of proteases. A proteolytic mechanism is also consistent with the rapid time-course of op-SRBC-triggered shedding, which is identical to that caused by LPS. Shedding by iIgG, conversely, demonstrates a lag at the earliest time-point. This lag is most likely because the cells must fall to the bottom of the well before they can be stimulated by iIgG. This sedimentation requirement is unique to iIgG, as LPS and op-SRBC have access to monocytes while they are still in suspension. This hypothesis is supported by the observations that op-SRBC and LPS stimulation have identical, early kinetics and that the CD163 expression of cells treated with op-SRBC or iIgG is nearly indistinguishable after the 1-h time-point.
Although LPS- and FcR-induced CD163 shedding is similar in a number of respects, they are not identical. For example, boiling the reagents responsible for stimulation completely abolishes FcR- but not LPS-triggered CD163 shedding. This is not surprising, as proteins such as Abs are denatured at high temperatures. This observation in conjunction with the fact that these reagents were tested for LPS before use demonstrate that the FcR-induced shedding described herein is not a result of LPS contamination.
A second difference between LPS- and FcR-induced shedding is that FcR, but not LPS, is inhibited by genistein, showing that FcR requires PTK activity to induce CD163 shedding. It is likely that genistein inhibits shedding by blocking the activity of the Src kinases responsible for phosphorylating the ITAMs found on FcRs [23
]. However, there are other important PTKs further downstream of ITAM activation, which may also be blocked by treatment with this inhibitor. In contrast to genistein, BIM I inhibits FcR and LPS shedding, suggesting that the two pathways converge at PKC. Although sensitivity to BIM I has been demonstrated for PMA-induced shedding [15
], this is a novel finding for FcR and LPS.
Although the kinetics of FcR- and LPS-triggered shedding are very similar within the first 3 h of stimulation, dramatic differences are seen at later time-points. Consistent with in vivo studies [17
], long-term LPS stimulation results in CD163 surface expression that is up-regulated up to threefold when compared with resting levels. This recovery of CD163 expression is IL-10-dependent, as it is completely inhibited by the addition of an anti-IL-10 mAb. In addition, augmented expression of IL-10 is measured following LPS treatment. In contrast to the effects observed following LPS treatment, CD163 expression fails to recover to baseline levels after 3 days of FcR stimulation. This is most likely a result of low IL-10 production.
In addition to the shedding of surface CD163 protein, experiments were performed to investigate the regulation of CD163 mRNA by various stimuli. When treated with IL-10, monocytes markedly up-regulate CD163 mRNA levels, and LPS treatment decreases CD163 mRNA expression. Both of these findings are consistent with previous reports [7
, 10
, 33
, 34
]. However, this paper also describes the novel finding that CD163 mRNA is suppressed by FcR stimulation, which is at least as potent as treatment with LPS. Furthermore, FcR stimulation completely counteracts the effect of IL-10, resulting in CD163 mRNA levels well below those of resting monocytes. These data suggest that in addition to causing the shedding of surface CD163, FcR stimulation may also inhibit the replacement of those molecules by inhibiting the synthesis of nascent CD163.
The effects of FcR stimulation on monocytes are multifaceted. FcRs trigger a number of proinflammatory and antimicrobial actions such as phagocytosis, superoxide production, and the release of inflammatory cytokines [21
]. However, FcRs have also been shown to have anti-inflammatory properties [25
, 35
36
37
38
39
]. It is of interest, therefore, that FcR cross-linking suppresses CD163 mRNA production and induces the shedding of surface CD163, a molecule associated with an anti-inflammatory monocyte phenotype.
Collectively, the results presented here suggest that the presence of immune complexes in disease states such as infection and autoimmunity may have previously unappreciated effects on monocyte phenotype and function. In addition, as CD163 mediates the uptake and degradation of free Hb-Hp complexes [4
, 5
], the effects of FcR activation may be even more important in conditions where immune complexes and high levels of free Hb coexist, such as in transfusion reactions, autoimmune hemolytic anemia, or infections by hemolytic bacteria. In these conditions, the elevated levels of circulating Hb may be exacerbated by the loss of surface CD163, potentially leading to a more severe clinical outcome.
Received October 30, 2003; revised February 24, 2004; accepted March 4, 2004.
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plus glucocorticoids stimulate the expression of a newly identified human mononuclear phagocyte-specific antigen J. Immunol. 140,2296-2304[Abstract] receptors in human atherosclerotic lesions Immunol. Lett. 77,169-174[CrossRef][Medline] RI and Fc RII induces secretion of tumor necrosis factor by human monocytes, requiring high affinity Fc-Fc R interactions.Functional activation of Fc RII by treatment with proteases or neuraminidase J. Immunol. 144,1304-1310[Abstract] converting enzyme (TACE) Ann. N. Y. Acad. Sci. 878,442-452[CrossRef][Medline] Nature 385,733-736[CrossRef][Medline] from cells Nature 385,729-733[CrossRef][Medline] receptor ligation J. Immunol. 166,4498-4506 receptor type I J. Exp. Med. 188,217-222 receptors J. Immunol. 166,6861-6868This article has been cited by other articles:
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