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Human tumors are frequently infiltrated by numerous monocytes/macrophages, which can be found within the tumor mass (intratumoral) or surrounding the tumor (peritumoral). The functional role that these monocytes/macrophages play in tumor growth is controversial. To address this issue we inhibited intratumoral monocyte/macrophage recruitment with mAbs that either blocked integrin function or neutralized a tumor-produced chemotactic protein. Both treatments significantly increased tumor formation and accelerated tumor growth. Surprisingly, the same results were obtained when recruitment of peritumoral or intratumoral monocytes/macrophages was blocked. Our findings are contrary to one of the purported roles of monocytes/macrophages, particularly in the peritumoral area, since we found no evidence for monocyte/macrophage-supported tumor growth. These results provide direct evidence that intratumoral as well as peritumoral monocytes/macrophages act to limit tumor size in the early stages following tumor inoculation and provide a mechanism that accounts for monocyte/macrophage recruitment to human tumors.
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BACKGROUND AND OBJECTIVE: Peripheral blood monocytes are a heterogeneous population, with phenotypes that change on activation or differentiation. Most of the monocytes express lipopolysaccharide (LPS) receptor, CD14 intensely, and do not express Fc gamma receptor III, CD16 (CD14++CD16- monocytes). But monocytes expressing CD16 with reduced CD14 (CD14+CD16+ monocytes) increase in inflammatory diseases as well as sepsis and bacteremia in hemodialysis patients. CD45RA is expressed on activated monocytes, and is regarded as an activation marker of peripheral blood monocytes. The purpose of this study was to determine the phenotypic and functional alteration of monocytes in periodontitis patients. METHODS: Peripheral blood was collected from 33 aggressive periodontitis patients (22 females, 11 males), 55 chronic periodontitis patients (35 females, 20 males) and 30 healthy subjects (16 females, 14 males), and the expression of CD14, CD16 and CD45RA on monocytes was determined using flow cytometry. The production of interleukin-6 (IL-6) by CD16+ and CD16- monocytes stimulated with LPS from Escherichia coli and Actinobacillus actinomycetemcomitans was also examined using flow cytometry. RESULTS: The percentage of CD14+CD16+ monocytes was significantly increased in chronic periodontitis patients. Percentage of monocytes expressing CD45RA was significantly increased in aggressive periodontitis patients compared to healthy subjects. CD16+ and CD16- monocytes produced IL-6 in response to LPS from E. coli and A. actinomycetemcomitans, and the percentage of IL-6 producing cells was higher in CD16+ monocytes than CD16- monocytes, suggesting that CD14+CD16+ monocytes represent a hyper-reactive phenotype. CONCLUSIONS: The present study demonstrated that CD14+CD16+ monocytes and CD45RA+ monocytes were increased in chronic and aggressive periodontitis, respectively. These findings suggest that alteration of monocytes in periodontitis patients could be evaluated by monitoring the surface expression of CD14, CD16 and CD45RA on monocytes.
Lipoprotein lipase (LPL) is made by several cell types, including macrophages within the atherosclerotic lesion. LPL, a dimer of identical subunits, has high affinity for heparin and cell surface heparan sulfate proteoglycans (HSPGs). Several studies have shown that cell surface HSPGs can mediate cell binding to adhesion proteins. Here, we tested whether LPL, by virtue of its HSPG binding could mediate monocyte adhesion to surfaces. Monocyte binding to LPL-coated (1-25 micrograms/mL) tissue culture plates was 1.4- to 7-fold higher than that of albumin-treated plastic. Up to 3-fold more monocytes bound to the subendothelial matrix that had been pretreated with LPL. LPL also doubled the number of monocytes that bound to endothelial cells (ECs). Heparinase and heparitinase treatment of monocytes or incubation of monocytes with heparin decreased monocyte binding to LPL. Heparinase/heparitinase treatment of the matrix also abolished the LPL-mediated increase in monocyte binding. These results suggest that LPL dimers mediate monocyte binding by forming a "bridge" between matrix and monocyte surface HSPGs. Inhibition of LPL activity with tetrahydrolipstatin, a lipase active-site inhibitor, did not affect the LPL-mediated monocyte binding. To assess whether specific oligosaccharide sequences in HSPGs mediated monocyte binding to LPL, competition experiments were performed by using known HSPG binding proteins. Neither antithrombin nor thrombin inhibited monocyte binding to LPL. Next, we tested whether integrins were involved in monocyte binding to LPL. Surprisingly, monocyte binding to LPL-coated plastic and matrix was inhibited by approximately 35% via integrin-binding arginine-glycine-aspartic acid peptides. This result suggests that monocyte binding to LPL was mediated, in part, by monocyte cell surface integrins. In summary, our data show that LPL, which is present on ECs and in the subendothelial matrix, can augment monocyte adherence. This increase in monocyte-matrix interaction could promote macrophage accumulation within arteries.
Human peripheral blood T cells lysed autologous or allogeneic monocytes, but not polymorphonuclear cells (PMN) or lymphocytes, in the presence of anti-CD3 (OKT3 (IgG2a) or anti-Leu 4 (IgG1)) monoclonal antibody (mAb). Other mAbs such as OKT4 (IgG2b), OKT8 (IgG2a), OKT11 (IgG2a), and OKM1 (IgG2a) did not mediate lysis of monocytes. Lysis of monocytes also did not occur in the presence of F(ab')2 fragments of OKT3 mAb. OKT3 mAb and control murine IgG2a mAb, but not F(ab')2 fragments of OKT3 mAb, were bound to the monocyte cell surface. Purified human IgG1 and IgG3 myeloma proteins, polyclonal human IgG, or Con A inhibited anti-CD3-dependent T-cell cytotoxicity against monocytes when added to the 4-hr 51Cr-release assay. Pretreatment of monocytes with an irrelevant murine IgG2a mAb also inhibited OKT3 mAb (IgG2a)-dependent lysis of these cells, but did not affect anti-Leu 4 mAb (IgG1)-dependent lysis, suggesting that two different Fc receptors were involved. These results strongly suggest that Fc IgG receptors on monocytes are a critical structure for anti-CD3-dependent cytotoxicity. Lysis of monocytes was accompanied by interleukin-1 (IL-1) production, which was detected in supernatants from 4-hr cultures of T cells and monocytes in the presence of the OKT3 mAb. Both anti-CD3-dependent lysis of monocytes and IL-1 production were severely decreased after treatment of T cells with either OKT3 or OKT8 mAb plus complement, but were not affected significantly by treatment with the OKT4 mAb plus complement. Purified CD8+ cells, prepared using the cell sorter, exhibited significant levels of anti-CD3-dependent monocyte lysis (greater than 10%). In contrast, purified CD4+ cells did not exhibit significant levels of anti-CD3-dependent cytotoxicity (less than 10%). Production of high concentrations of IL-1 was observed in cultures of purified CD8+ cells and monocytes in the presence of anti-CD3 mAb. Only low concentrations of IL-1 were detected in cultures of purified CD4+ cells, monocytes, and OKT3 mAb. These results suggest that CD8+ cells are primarily responsible for lysis of monocytes, which is associated with IL-1 production. It appears that anti-CD3 mAb brings CD8+ T cells and monocytes into close proximity by binding to the CD3 antigen on T cells and to the Fc IgG receptor on monocytes. This interaction results in lysis of monocytes primarily by CD8+ cells, after bypassing any antigen recognition requirements that may be otherwise needed. Lysis of monocytes appears to be associated with IL-1 release.
Complement receptor 1 (CR1) on primate red blood cells (RBC) binds most complement-fixing immune complexes in the circulation. It has been postulated that by binding them, RBC keep immune complexes in the intravascular space and deliver them to the tissue macrophages of the mononuclear phagocyte system. We have developed an in vitro model to study the transfer of RBC-bound immune complexes (heat-aggregated IgG and DNA-anti-DNA) to phagocytic cells (human monocytes). Transfer of immune complexes from RBC to monocytes occurred significantly more rapidly than monocyte uptake of the same immune complexes from solution. In the transfer process, complex-bearing RBC were not bound or sequestered by the monocytes. To define the monocyte receptors involved in binding immune complexes from the RBC surface, monocyte receptors were blocked with MoAbs (anti-CR1, anti-FcRII) or EDTA (to block CR3). Monocyte binding of immune complexes primarily used CR1 with a small contribution from FcRII, and with little or no contribution from CR3 and FcRI. Uptake of immune complexes from solution employed the same monocyte receptors as binding of complexes from the RBC surface. Immune complexes in solution bound to RBC and to monocytes with equally high avidity (approximately 1 x 10(11) l/M), but monocytes expressed a 15-20-fold greater number of immune complex binding sites. We propose that immune complexes distribute between RBC and monocytes according to the binding capacity of these cells, such that at equal or high RBC/monocyte ratios as would be seen in the circulation immune complexes bind to RBC, but at low RBC/monocyte ratios (as would be seen in the sinusoidal circulation of the liver and spleen), most immune complexes bind to monocytes. To define the pathway by which immune complexes move from RBC to monocytes, their release from RBC CR1 was examined. Under various conditions, the dissociation rate was extremely slow, and did not increase with the addition of monocyte supernatants. To examine whether factor I-mediated processing of immune complexes enhances binding of immune complexes to monocytes, RBC-bound complexes were released with factor I, and binding of these 'processed' immune complexes to monocytes was examined. Monocyte binding of these processed immune complexes was slower than of control ones; furthermore, performance of transfer experiments at 4 degrees C, which significantly shows enzymatic processes, did not decrease the rate of immune complex transfer from RBC to monocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
Human blood monocytes in culture gradually lose their capability to produce superoxide when stimulated. Addition of 10(-8) M 1,25-dihydroxyvitamin D3 [1, 25(OH)2D3], 2.5 ng/ml LPS, or 25 ng/ml lipotechoic acid (LTA) prevented this decrease in monocyte respiratory burst when added at initiation of culture. Monocytes cultured for 4 days in the presence of 1,25 (OH)2D3, LPS, or LTA retained the ability to produce superoxide and 1,25 (OH)2D3 actually increased the oxidative capacity compared with fresh monocytes. Furthermore, addition of 1,25(OH)2D3, LPS, or LTA to monocytes at day 4 of culture restored the oxidase activity by day 7 to the levels seen with fresh monocytes. Cytosol or membrane fractions from monocytes cultured with or without the agents indicated above were tested in a cell-free assay of superoxide production by mixing with fresh monocyte membrane or cytosol fractions, respectively. Membrane oxidase activity from these cultured monocytes showed only minimal changes regardless of the agent present or absent from the culture. However, the activity of cytosol fractions from these same cultured monocytes showed substantial differences depending upon the culture conditions and these changes correlated closely with changes in activity of the intact monocytes from which the cytosols were derived. Immunoblot analysis of monocyte membranes and cytosol was used to assess the amount of the 91-kDa and 22-kDa subunits of membrane oxidase cytochrome 558 (gp91 and p22), and the 47-kDa and 67-kDa cytosol oxidase factors (p47 and p67) in the different culture conditions. The gp91 and p22 decreased during culture of monocytes, although the decrease was only apparent by 7 days in culture. When 1,25 (OH)2D3, LPS, or LTA were present at the initiation of culture, then an increase in gp91 and p22 was seen as compared with fresh monocytes at day 4. When these agents were added at day 4 of culture, the levels of gp91 and p22 at day 7 were similar to fresh monocytes. The p67 cytosol oxidase component showed little change in amount by immunoblot regardless of the time in culture or whether 1,25(OH)2D3, LPS, or LTA were present. In contrast, the p47 cytosol oxidase factor decreased by day 4 of culture and was markedly depressed by day 7. Monocytes cultured in the presence of either 1,25(OH)2D3, LPS, or LTA preserved the expression of p47, whereas addition of these agents to monocytes at day 4 of culture restored the expression of p47 by day 7 to the level of fresh monocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
The suppressive effects of hydrocortisone (HC) on the human immune system are well known. The mediation of the immunosuppressive effects of HC on lymphocyte responses via inhibition of monocyte function has been examined by monocyte-dependent, antigen-induced lymphocyte proliferation. Monocytes that were first treated with HC and then washed were unaffected in their subsequent ability to present antigen. However, there was a dramatic inhibition of lymphocyte proliferative responses if HC was present while monocytes were pulsed with antigen. This was directly related to the dose of HC present. HC-mediated inhibition of monocyte antigen presentation could not be overcome by the addition of interleukin-1 (IL-1) to cultures, and thus inhibition of monocyte IL-1 secretion cannot totally account for the inhibition of monocyte antigen presentation. Although HC inhibits monocyte antigen presentation, HC increases the expression of HLA-DR antigens on monocytes. Other monocyte stimulants, including lipopolysaccharide (LPS), lymphokine, and gamma interferon, were examined for their effect on monocyte DR expression and their effect on monocyte antigen presentation. No correlation was found between the ability to increase monocyte DR antigen expression and the effect on antigen presentation. While HC, lymphokine, and gamma interferon all increased the expression of DR antigens on monocytes, HC, LPS, and lymphokine, but not gamma interferon, inhibited monocyte antigen presentation. Although HC can exert profound immunosuppressive effects via monocytes, it is not the only mechanism of inhibition. HC added to cultures after monocytes had been pulsed with antigen was also inhibitory.
We examined the effect of interleukin 2 (IL 2) on the capacity of human monocytes to secrete reactive oxygen species triggered via Fc-gamma receptor (Fc gamma R) function as measured by chemiluminescence (CL). IL 2 did not activate highly purified (hp) monocytes to respond to Fc gamma R-mediated phagocytic stimulation with an enhanced respiratory burst activity, unless low numbers of T lymphocytes had been cocultured with hp monocytes. The degree of monocyte activation in peripheral blood mononuclear cells (PBMC) by IL2 was dependent on T lymphocytes to monocytes ratios as well as on IL 2 concentrations. Optimal Fc gamma R function was detected with IL 2 concentrations of 60 to 600 U/ml and one to two T lymphocytes per monocyte, whereas higher cellular ratios were suppressive. Supernatants from IL 2-treated PBMC contained interferon-gamma (IFN-gamma) and monocyte activating factor (MAF) activity (= enhanced monocytic Fc gamma R mediated CL). The secretion of both cytokine activities was strongly enhanced by a cooperative function of monocytes. The correlation of IL 2-induced secretion of IFN-gamma and MAF activity was striking; however, monoclonal anti-IFN-gamma antibodies failed to abrogate IL 2-stimulated and lymphocyte-dependent monocyte activation. Although IL 2 had no direct monocyte activating effect, pretreatment of hp monocytes with IL 2 led to a monocyte priming: subsequent coculture with autologous control T lymphocytes enhanced the monocyte Fc gamma R-mediated CL response. The priming of monocytes by IL 2 was dependent on the interaction of IL 2 with the monocytic IL 2 receptor, as shown by inhibition experiments with anti-IL 2 receptor monoclonal antibodies. Thus, we observed an IL 2-driven monocyte/T lymphocyte interaction leading to an increased Fc gamma R-mediated monocytic respiratory burst activity and to the secretion of a soluble MAF activity, but there were no detectable amounts of IFN-gamma.
Peripheral blood monocytes seem to be of importance in the initiation and maintenance of cutaneous inflammatory disorders such as psoriasis and atopic dermatitis. Functional abnormalities of monocytes have been observed in both diseases. We sought to determine whether these abnormalities are reflected by an altered phenotypic expression of functionally active surface molecules. Peripheral blood monocyte subsets varying in cellular density and cell size from patients with psoriasis and atopic dermatitis were investigated using FACS analysis employing a panel of monoclonal antibodies (CD14, CD16, HLA-DR, HLA-DO, Fc epsilon RII, IL-2R, ICAM-1, CR3). Furthermore, the modulation of expression by interferon-gamma in monocyte subsets from patients was compared to normal controls. The results show that HLA-DR and -DQ expression on monocyte subsets in psoriatic patients was significantly decreased; "large" monocytes expressed significantly less HLA-DR than "small" monocyte subpopulations. Decreased HLA-DR and -DQ expression could be upregulated by incubation of psoriatic monocytes with IFN gamma. In atopic dermatitis, a different phenotype pattern of monocyte subsets was demonstrated: HLA-DR expression and HLA-DQ expression were both decreased in both "large" and "small" monocytes as compared to normal controls. However, there were no significant differences in HLA-DR and HLA-DQ expression between "large" and "small" monocyte subpopulations in atopic dermatitis. Moreover, the ICAM-1 and IL-2R expression of "large" and "small" monocyte subpopulations was significantly decreased in atopic patients from levels in normal controls and psoriatic patients. The altered expression of HLA-DR, -DQ ICAM-1 and IL-2R could be upregulated by incubation of atopic monocytes with IFN gamma. In addition, there was a significant increase in the percentage of monocytes in the differential count of patients with psoriasis or atopic dermatitis. We conclude that the differential phenotype pattern of surface molecules on monocytes in psoriasis and atopic dermatitis may reflect an abnormal monocyte maturation/differentiation state. This may explain the functional abnormalities of monocytes observed in patients with psoriasis and atopic dermatitis.
The regulatory influence of autologous blood monocytes on the PWM-induced generation of Ig-secreting cells was assessed using a reverse haemolytic plaque forming cell (PFC) assay. The PWM-induced PFC responses of monocyte-depleted cells were low or absent in most cases. Addition of 12-42% freshly isolated monocytes fully reconstituted the IgM-, IgG- and IgA-PFC responses. With more monocytes added, the PFC responses declined. Monocytes precultured for 48 h supported the PFC responses of monocyte-depleted cells less well and addition of monocytes stimulated with phorbol myristate acetate (PMA) did not increase the response. The low responses of monocyte-depleted cells co-cultured with precultured monocytes were not increased by addition of supernatant from monocyte cultures. The PFC responses of mononuclear cells induced by PWM were significantly inhibited by unstimulated precultured monocytes, and to a larger degree by PMA-treated monocytes, indicating the presence of suppressor cells among the precultured monocytes. The PWM-induced thymidine incorporation by monocyte-depleted cells with precultured monocytes added was only slightly lower than that obtained with freshly isolated monocytes added, suggesting that the suppressive role of precultured monocytes was not due to cytotoxicity.
Previous studies reported that Fusobacterium nucleatum induced polyclonal B-lymphocyte activation (PBA) as determined by immunoglobulin M production in cultures of human peripheral blood mononuclear cells. However, the PBA response was greatly enhanced when the cells were depleted of esterase-positive, adherent cells (i.e., monocytes). The purpose of this study was to confirm and further examine the suppression of F. nucleatum-induced PBA (F. nucleatum-PBA) by blood monocytes. For comparison, PBA induced by pokeweed mitogen (PWM-PBA), which is enhanced by monocytes, was assessed in some experiments. We found the removal of monocytes from unfractionated cells by (i) Sephadex G-10, (ii) anti-monocyte specific OM-1 monoclonal antibody plus complement, or (iii) L-leucine methyl ester, a compound which selectively kills lysosome-rich cells, resulted in a population of cells responsive to F. nucleatum-PBA and unresponsive to PWM-PBA. The addition of double adherence-purified monocytes (greater than 85% esterase-positive cells), particularly in concentrations of greater than 10%, to lymphocytes depleted of monocytes by G-10, OM-1, or L-leucine methyl ester treatments, suppressed F. nucleatum-PBA and enhanced PWM-PBA. Monocytes also suppressed a mixture of isolated T and B cells combined in a T/B cell ratio of 3:1, which is an optimal ratio for F. nucleatum-PBA. Allogeneic monocytes suppressed F. nucleatum-PBA, although at low numbers these cells were not as suppressive as autologous monocytes. Heating at 56 degrees C for 15 min, sonicating, or freeze-thawing the monocyte preparations resulted in an abrogation of monocyte-induced suppression of F. nucleatum-PBA. Kinetic studies in which fresh monocytes were added daily to lymphocytes stimulated with F. nucleatum or PWM showed that the monocytes must be added within the first 2 days of culture to suppress F. nucleatum-PBA or enhance PWM-PBA. Monocytes incubated with F. nucleatum for 48 h released into the culture medium a soluble factor that suppressed F. nucleatum-PBA. The results from this study demonstrate a potent mechanism by which the host might prevent exaggerated nonspecific immunoglobulin responses when exposed to PBA-inducing concentrations of F. nucleatum. On the other hand, the induction of suppressive monocytes (or monocyte-mediated suppressive factors) by interaction with F. nucleatum might result in the inhibition of host protective immune reactions.
This study examined the adhesive interaction of peripheral blood monocytes with VCAM-1 and analyzed the effect of P-selectin binding to monocytes on the adhesive interaction with VCAM-1 under flow conditions. P-selectin glycoprotein ligand-1 is expressed on most monocytes. Furthermore, most monocytes bind soluble P-selectin derived from platelets. P-selectin binding to monocytes did not alter the amount of expression of alpha4 integrin on monocytes. However, the mean channel fluorescence value for binding Cy2-conjugated soluble VCAM-1 to P-selectin-bound monocytes was slightly more than that for binding Cy2-conjugated soluble VCAM-1 to untreated monocytes. Under flow conditions, the number of P-selectin-bound monocytes bound to VCAM-1 was much higher than that of untreated monocytes bound to VCAM-1. These bindings were abolished by pretreatment of untreated monocytes and P-selectin-bound monocytes with anti-VCAM-1 mAb or anti-alpha4 integrin mAb. Furthermore, P-selectin binding to monocytes increased shear resistance and thus increased the adhesive strength of monocytes to VCAM-1. These findings indicate that P-selectin binding to monocytes enhances the adhesive interaction of monocytes with VCAM-1. It is suggested that P-selectin glycoprotein ligand-1/P-selectin interaction and alpha4 integrin/VCAM-1 interaction can act sequentially in the adhesion cascade that regulates monocyte trafficking to inflammatory and atherosclerotic lesion.
OBJECTIVE: CD16 (IgG Fcgamma receptor type IIIA [FcgammaRIIIA])-expressing CD14+ monocytes express high levels of Toll-like receptor 2 (TLR-2) and are able to efficiently produce proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha). To understand the role of CD16 and TLR-2 in monocyte and macrophage activation in rheumatoid arthritis (RA), we investigated the expression of TLR-2 on CD16+ blood monocytes and synovial tissue macrophages and the effect of CD16 and TLR-2 activation on cytokine production. METHODS: The expression of CD14, CD16, TLR-2, and TLR-4 on blood monocytes was measured by flow cytometric analysis. CD16 and TLR-2 expression in RA synovial tissue was detected by 2-color immunofluorescence labeling. CD16+ mature monocytes were prepared by incubating blood monocytes in plastic plates for 24 hours. These adhered monocytes were stimulated with lipoteichoic acid (LTA), anti-FcgammaRIII antibody, and Hsp60 for 5 hours, and culture supernatants were measured for various cytokines by immunoassay. The activation of NF-kappaB was detected by electrophoretic mobility shift assay. RESULTS: The frequency of CD16+ cells in all blood monocytes was significantly increased in patients with RA compared with healthy controls. TLR-2 was expressed at higher levels on CD16+ monocytes than on CD16- monocytes, while TLR-4 was expressed similarly on both monocytes. In RA synovial tissue, CD16+/TLR-2+ cells were distributed mainly in the lining layer. TLR-2 expression on monocytes was enhanced by macrophage colony-stimulating factor (M-CSF) and interleukin-10 (IL-10), but was reduced by transforming growth factor beta1, while CD16 expression was inducible by these cytokines. Adhered monocytes ( approximately 50% CD16+) produced TNFalpha, IL-1beta, IL-6, IL-8, IL-12 p40, IL-1 receptor antagonist, and IL-10 after LTA stimulation. This cytokine response was inhibited significantly by anti-TLR-2 antibody and partly by anti-TLR-4 antibody. Anti-FcgammaRIII antibody stimulation markedly enhanced the LTA-induced TNFalpha response. Hsp60 could stimulate TNFalpha production by adhered monocytes, which was inhibited similarly by anti-TLR-2 antibody and anti-TLR-4 antibody. NF-kappaB activation in adhered monocytes was induced by LTA, but this NF-kappaB activity was not augmented by anti-FcgammaRIII antibody stimulation. CONCLUSION: These results suggest that CD16+ monocytes and synovial tissue macrophages with high TLR-2 expression may be induced by M-CSF and IL-10, and their production of TNFalpha could be simulated by endogenous TLR ligands such as Hsp60 and FcgammaRIIIA ligation by small immune complexes in RA joints.