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PubMed1999

Urokinase plasminogen activator receptor (CD87) expression of tumor-associated macrophages in ductal carcinoma in situ, breast cancer, and resident macrophages of normal breast tissue.

UNLABELLED: Macrophages concentrate urokinase-type plasminogen activator (uPA) at the cell surface by expressing urokinase receptors (uPAR) in order to focus the pericellular space plasminogen-dependent proteolysis important in matrix remodeling and cell movement. This study examines the uPAR levels of tumor-associated macrophages (TAM) of invasive breast carcinomas, of TAMs from ductal carcinoma in situ (DCIS) and of macrophages derived from normal (non-tumor) breast tissue. TAMs from invasive breast carcinomas (n = 30), from DCIS (n = 12), and macrophages from normal breast tissue (n = 30) were cultured and immunocytochemically phenotyped by using a panel of antibodies. Urokinase receptor levels were determined by Western blot analysis and in cell-free supernatants by enzyme-linked immunosorbent assay. Urokinase receptor cell surface fluorescence intensity was determined by FACS and by confocal laser scan microscopy. Urokinase-receptor mRNA was detected by in situ hybridization. TAMs of invasive breast carcinomas and of DCIS possess significantly elevated uPAR levels compared with macrophages derived from normal breast tissue. CONCLUSIONS: activated macrophages with elevated uPAR levels belong to inflammatory areas in close vicinity of infiltrating and non-infiltrating (DCIS) tumor cells. Blood monocytes that possess elevated uPAR-levels may be selectively recruited from the bloodstream to inflammatory sites close to carcinoma cells, and/or breast cancer and precursor lesions may induce elevated uPAR-levels in TAMs by paracrine interactions.

Breast Neoplasms↗
PubMed2000

Lack of IL-10 synthesis by murine alveolar macrophages upon lipopolysaccharide exposure. Comparison with peritoneal macrophages.

The central role of alveolar macrophages in the establishment of lipopolysaccharide (LPS)-induced lung inflammation is well demonstrated. They produce and release numerous proinflammatory molecules, among which is tumor necrosis factor alpha (TNF-alpha), a cytokine responsible in part for the neutrophilic alveolitis. Interleukin-10 (IL-10) produced by LPS-activated mononuclear phagocytes is a major anti-inflammatory cytokine that down-regulates TNF-alpha synthesis. We studied the ability of murine alveolar macrophages to produce IL-10 in vivo and in vitro, in response to LPS. Unexpectedly, the IL-10 protein was not detected in the whole lung and airspaces after LPS intranasal instillation. In addition, no IL-10 protein was found in supernatants of isolated and LPS-stimulated alveolar macrophages. The lack of IL-10 synthesis was confirmed by the absence of specific RNA transcripts. By contrast and as expected, autologous peritoneal macrophages produced IL-10 upon LPS challenge. Drugs that usually modify the TNF-alpha/IL-10 balance in favor of IL-10 were used without success. Thus, maneuvers allowing an increase in intracellular cAMP concentrations did not reverse this unexpected phenotype. Moreover, direct activation of protein kinase C with PMA was unable to trigger IL-10 formation by alveolar, by contrast to peritoneal, macrophages. The current findings describe a specific phenotype for murine alveolar macrophages during LPS-induced inflammation.

Animals↗
PubMed1996

Vitamin D3-binding protein as a precursor for macrophage activating factor in the inflammation-primed macrophage activation cascade in rats.

When rat peritoneal nonadherent cells were treated with inflammatory lipid metabolites and cultured with adherent cells in 1% fetal calf serum (FCS) supplemented medium RPMI 1640 (FCS medium) for 3 hr, markedly enhanced phagocytic and superoxide generating capacities of macrophages were observed. Stepwise preparation of conditioned medium of lysophosphatidylcholine (lyso-Pc)-treated B cells and untreated T cells in FCS medium generated a potent macrophage activating factor whereas cultivation of lyso-Pc-treated B cells alone in a 1% adult rat serum supplemented medium efficiently generated the macrophage activating factor. Generation of macrophage activating factor requires a precursor protein, serum vitamin D3-binding protein (DBP), as well as participation of lymphocyte glycosidases. The lyso-Pc-inducible beta-galactosidase of B lymphocytes and the Neu-1 sialidase of T lymphocytes modified bovine DBP (bDBP) to yield the macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar. In contrast, lyso-Pc-inducible beta-galactosidase of B cells alone modified rat DBP (rDBP) to yield the macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar. Thus, we conclude that bDBP carries a trisaccharide composed of N-acetylgalactosamine, galactose, and sialic acid while rDBP carries a disaccharide composed of N-acetylgalactosamine and galactose.

Animals↗
PubMed1996

Interleukin 2 down-modulates the macrophage colony-stimulating factor receptor in murine macrophages.

Macrophage colony-stimulating factor (M-CSF) is the main growth factor for mononuclear phagocytes. Responsiveness to growth factors is reduced in the course of functional activation of macrophages. We studied the interference of the macrophage activator interleukin 2 (IL-2) with the response to M-CSF, in macrophages of the M-CSF-dependent murine line BAC-1.2F5. Long-term effects of IL-2 on cell growth were determined, showing that IL-2 reduces the M-CSF-dependent proliferation of macrophages. Short-term effects of IL-2 on the expression of the receptor for M-CSF (M-CSF.R) were characterized in more detail. IL-2 rapidly down-modulated M-CSF.R in a dose-dependent fashion, and interferon-gamma and lipopolysaccharides synergized with IL-2 in this modulation. The IL-2-induced down-modulation of M-CSF.R was shown to require the activity of protein-kinase-C and phospholipase-C. The data are consistent with the hypothesis that the down-modulation of M-CSF.R is a general property of macrophage activators.

Animals↗
PubMed2001

Membrane macrophage colony-stimulating factor on MADB106 breast cancer cells does not activate cytotoxic macrophages but immunizes rats against breast cancer.

Weakly immunogenic, but highly malignant, rat MADB106 breast cancer cells were retrovirally transduced with the membrane form of macrophage colony-stimulating factor (mM-CSF). The cloned mM-CSF-transfected MADB106 cells physically conjugated with macrophages, but were not killed by the macrophages in 48-h cytotoxicity assays. Macrophages killed the mM-CSF-expressing tumors in the presence of noncytotoxic doses of either taxol or taxol plus cisplatin. This indicated that macrophages bind to the mM-CSF expressed on the tumor cells, but for successful macrophage cytotoxicity to occur against mM-CSF-transduced tumor cells other factors must be present. The mM-CSF-transfected tumor cells were rejected when inoculated subcutaneously into normal rats. Cloned MADB106 tumor cells which expressed high amount of mM-CSF were rejected, while tumor cells that displayed lower levels of mM-CSF grew in 60% of the inoculated rats. The mM-CSF-transfected tumors that grew were smaller and had a greater amount of necrosis, compared to the viral vector tumors. Rats that spontaneously rejected the mM-CSF-transfected MADB106 cells showed rechallenge resistance to unmodified parental MADB106 and R3230Ac breast cancers, but not to the F98 glioma. These observations suggest that breast cancer-specific immunity was induced by the inoculation of mM-CSF-expressing MADB106 tumor cells.

Animals↗
PubMed1983

In vitro immune response to sheep erythrocytes in macrophage depleted cultures. Restoration with interleukine 1 or a monokine from resident macrophages and stimulation by N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP).

The involvement of macrophages in the adjuvanticity of N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) has been examined. The stimulation of the in vitro primary immune response to sheep red blood cells (SRBC) has been studied, because it is known that macrophages cooperate through the mediation of soluble compounds for the induction of the anti-SRBC response. The cultures depleted of macrophages by passing spleen cells on Sephadex G-10 were unable to give any response to SRBC. Their immune responsiveness was fully restored by the addition of either Interleukine 1 (IL 1) obtained from P388D1 cells or a factor able to replace macrophages (FRM) obtained from resident peritoneal macrophages. MDP alone, at any dose, was unable to induce any response in such macrophage depleted cultures, but it was able to enhance the antibody response of these cultures reconstituted with monokines, with the same characteristics in dose effect and timing dependence than in whole spleen cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Impairment of macrophage migration inhibitory factor synthesis and macrophage migration in protein-malnourished mice.

Weanling CD2F1 mice were fed isocaloric diets that were protein sufficient (PS; containing 27% casein) or protein deficient (PD; containing 8% casein). Weight measurements demonstrated that the growth of PD mice was significantly impaired, thus indicating that the PD diet induced protein malnutrition. The cellular immune responsiveness of these mice was assessed from Day 21 to Day 49 of the diet using, as indicators, in vitro production of migration inhibitory factor (MIF) by splenic lymphocytes and MIF responsiveness of peritoneal macrophages. PD lymphocytes, when stimulated with the polyclonal activator concanavalin A, produced significantly less MIF than did PS lymphocytes. The amount of MIF produced by PD lymphocytes, however, increased throughout the study, possibly indicating delayed maturation of MIF synthetic capacity in PD mice. Normal CD2F1 mouse macrophages were used for these assays. MIF responsiveness of PD and PS macrophages was not significantly different when assayed using MIF produced by normal CD2F1 mouse lymphocytes. As compared to that of PS macrophages, the migratory ability of PD macrophages decreased progressively throughout the study. This impaired migratory ability did not interfere with MIF responsiveness of PD macrophages.

Animals↗
PubMed1986

A simple and rapid method for the determination of macrophage activating factor involving a new type of apparatus suitable for the measurement of macrophage chemiluminescence.

A simple and rapid method for the determination of macrophage activating factor is described. A new type of apparatus suitable for the measurement of macrophage chemiluminescence was devised, and the effect of lymphokines on macrophage activities was studied by measuring phorbol myristate acetate-induced luminol-dependent chemiluminescence. An outstanding feature of the new apparatus is that the plastic dish used for the cell culture can be used as the vessel for the chemiluminescence reaction. When thioglycollate-elicited ICR mouse peritoneal macrophages were incubated with lymphokines, their ability to generate chemiluminescence increased rapidly, reaching a maximal level at about 4 h, and then it progressively decreased to the control level at 8 h. Although this increasing effect of lymphokines on macrophage chemiluminescence was short-lived, it could be seen at a relatively low concentration, at which lymphokine-mediated cytotoxic activity of macrophages was not observed.

Animals↗
PubMed1984

Immunoregulation by macrophages. III. Prostaglandin E suppresses lymphocyte activation but not macrophage effector function during Salmonella enteritidis infection.

Peritoneal macrophages obtained during primary or secondary infection with Salmonella enteritidis differ in the proportions of subpopulations with the capacity to secrete prostaglandin E (PGE) and interleukin 1 (IL1) and have bactericidal and tumoricidal activities in vitro. Using indomethacin in vivo and PGE in vitro we have studied the regulation of subpopulations of lymphocytes and macrophages by PGE during the inflammatory reaction. Indomethacin treatment promoted clearance of the Salmonella and a 50-90% increase in macrophages recovered from the peritoneal cavity in both primary and secondary infected animals. Whilst blocking the capacity of macrophages to secrete PGE in vitro the indomethacin treatment did not alter their bactericidal (or tumoricidal) activity nor their cyclic AMP response to PGE2. A major effect of indomethacin in vivo and of PGE2 in vitro however, was on the production and expression of IL1 and IL2. Secretion of IL1 by macrophages in vitro was greatly enhanced in indomethacin treated mice and was suppressed in vitro by PGE2. Prostaglandin E2 also inhibited IL1 dependent T-lymphocyte differentiation. IL2 secretion and IL2 dependent blast cell proliferation in vitro and sensitivity of the cells to PGE2 inhibition increased through this sequence of reactions. Lymphocyte populations harvested at intervals during primary or secondary infection differed in their cyclic AMP response to PGE2 and in IL2 secretion in vitro. This may be related to changes in the proportions of lymphocyte subsets having Lyt 1+ markers. We conclude that peritoneal macrophages from Salmonella infected mice differ in their capacity to secrete PGE and IL1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2026

Next-generation macrophage engineering in cancer therapy: From TAM reprogramming to CAR-macrophages.

Macrophages are central regulators of the tumor microenvironment (TME), shaping immune suppression, angiogenesis, metabolism, and therapeutic resistance in solid cancers. While early strategies sought to deplete tumor-associated macrophages (TAMs) or block monocyte recruitment, limited efficacy and compensatory mechanisms revealed the need for functional reprogramming rather than elimination. Recent advances in viral vectors, CRISPR-Cas genome editing, and RNA-based delivery platforms have enabled precise genetic modification of macrophages, giving rise to chimeric antigen receptor macrophages (CAR-Ms) and related engineered products. Beyond antigen targeting, effective macrophage engineering requires stabilization of pro-inflammatory identity, resistance to tumor-induced repolarization, metabolic reinforcement, and integration of checkpoint modulation pathways. This review synthesizes current strategies across DNA, mRNA, and siRNA-based platforms, highlighting convergent design principles that connect TAM reprogramming with CAR-M development. We discuss reshaping phagocytosis checkpoints, metabolic and transcriptional stabilization, cytokine augmentation, and synthetic receptor architecture, emphasizing combinatorial and context-aware engineering, while proposing new candidate gene targets. Engineered macrophages are thus evolving from simple effector cells into programmable immune coordinators capable of converting immunologically "cold" tumors into inflamed, therapy-responsive niches.

CAR-M↗
PubMed1989

Activation of macrophages to express cytocidal activity correlates with inhibition of their responsiveness to macrophage colony-stimulating factor (CSF-1): involvement of a pertussis toxin-sensitive reaction.

Bone marrow-derived murine macrophages were used to study the relationship between the proliferative response of macrophages to macrophage colony-stimulating factor (CSF-1) and their activation for cytocidal activity against tumour cells. Macrophage activation required two sequential signals. Lymphokines (gamma interferon, interleukin-4) provided the first (priming) signal; bacterial products (lipopolysaccharide, lipophilic muramyl tripeptide, lipopeptide 31362, pertussis toxin) provided the second (triggering) signal. Both priming and triggering agents inhibited [3H]-thymidine uptake by macrophages stimulated with CSF-1. The antiproliferative activity of priming and triggering stimuli was synergistic. Pretreatment with triggering stimuli at 37 degrees C caused a rapid reduction of the subsequent binding of [125I]-CSF-1 to the cell surface at 4 degrees C, whereas priming agents had relatively little effect. Growth inhibition by both priming and triggering agents was largely reversible by washing the cells, and occurred even when they were added as long as 24 h after the growth factor. The ability of pertussis toxin to both inhibit CSF-1-induced proliferation and trigger cytotoxicity in macrophages suggests the involvement of a regulatory GTP-binding protein (G protein) in both processes.

Animals↗
PubMed1990

Synergistic activation of 2-deoxy-D-glucose uptake in rat and murine peritoneal macrophages by human macrophage colony-stimulating factor-stimulated coupling between transport and hexokinase activity and phorbol-dependent stimulation of pentose phosphate-shunt activity.

1. Transport and accumulation of 2-deoxy-D-glucose (2dGlc) in rat and murine peritoneal macrophages were investigated by using C-1-3H-labelled and C-2,6-3H-labelled 2dGlc. 2. There was active accumulation of both C-1- and C-2,6-labelled 2dGlc by quiescent rat and murine macrophages via a phloretin-inhibitable transport system. 3. The rate of uptake and accumulation of 2dGlc (C-1 label) was increased by exposure to human macrophage colony-stimulating factor (mCSF-1) (1000 units/ml) in both murine and rat macrophages. This indicates that mCSF-1 enhances coupling between hexokinase activity and glucose transport at the endofacial surface of the transporter. 4. Phorbol 12-myristate 13-acetate ('phorbol') at 40 nM stimulated 2dGlc in rat macrophages entirely by increasing the C-2,6 label uptake. This indicates that phorbol stimulates 2dGlc uptake mainly by increasing the activity of the pentose phosphate pathway. 5. Simultaneous exposure to phorbol and mCSF-1 stimulates 2dGlc uptake to a greater extent than found with either phorbol or mCSF-1 alone. This result is explained by a simultaneous enhancement of pentose phosphate-pathway activity and of hexokinase activity acting at the endofacial surface of the cell membrane. The dual activation of these serial processes coupled to the loss of the reaction products of the pentose phosphate-shunt pathway from the cells in the form of reactive oxygen intermediates, protons and CO2 could explain the synergistic action of phorbol and mCSF-1 in activation of sugar transport in macrophages.

Animals↗
PubMed1998

Production of adrenomedullin in macrophage cell line and peritoneal macrophage.

We demonstrate that adrenomedullin (AM) is produced and secreted from cultured murine monocyte/macrophage cell line (RAW 264.7) as well as mouse peritoneal macrophage. Immunoreactive (IR) AM secreted from RAW 264.7 cells was chromatographically identified to be native AM. To elucidate the regulation mechanism of AM production in macrophage, we examined the effects of various substances inducing differentiation or activation of monocyte/macrophage. Phorbol ester (TPA), retinoic acid (RA), lipopolysaccharide (LPS), and interferon-gamma (IFN-gamma) increased AM production 1.5-7-fold in RAW 264.7 cells in a dose- as well as time-dependent manner. By LPS stimulation, the AM mRNA level in RAW 264.7 cells was augmented up to 7-fold after 14 h incubation. RA exerted a synergistic effect when administered with TPA, LPS, or IFN-gamma, whereas IFN-gamma completely suppressed AM production in RAW 264.7 cells stimulated with LPS. Dexamethasone, hydrocortisone, estradiol, and transforming growth factor-beta dose-dependently suppressed AM production in RAW 264.7 cells. AM production was also investigated in mouse peritoneal macrophage. Primary mouse macrophage secreted IR-AM at a rate similar to that of RAW 264.7 cells, and its production was enhanced 9-fold by LPS stimulation. AM was found to increase basal secretion of tumor necrosis factor alpha (TNF-alpha) from RAW 264.7 cells, whereas AM suppressed the secretion of TNF-alpha and interleukin-6 from that stimulated with LPS. Thus, macrophage should be recognized as one of the major sources of AM circulating in the blood. Especially in cases of sepsis and inflammation, AM production in macrophage is augmented, and the secreted AM is deduced to function as a modulator of cytokine production.

Adrenomedullin↗
PubMed1996

Granulocyte macrophage colony stimulating factor produced in lesioned peripheral nerves induces the up-regulation of cell surface expression of MAC-2 by macrophages and Schwann cells.

Peripheral nerve injury is followed by Wallerian degeneration which is characterized by cellular and molecular events that turn the degenerating nerve into a tissue that supports nerve regeneration. One of these is the removal, by phagocytosis, of myelin that contains molecules which inhibit regeneration. We have recently documented that the scavenger macrophage and Schwann cells express the galactose-specific lectin MAC-2 which is significant to myelin phagocytosis. In the present study we provide evidence for a mechanism leading to the augmented expression of cell surface MAC-2. Nerve lesion causes noneuronal cells, primarily fibroblasts, to produce the cytokine granulocyte macrophage-colony stimulating factor (GM-CSF). In turn, GM-CSF induces Schwann cells and macrophages to up-regulate surface expression of MAC-2. The proposed mechanism is based on the following novel observations. GM-CSF mRNA was detected by PCR in in vitro and in vivo degenerating nerves, but not in intact nerves. The GM-CSF molecule was detected by ELISA in medium conditioned by in vitro and in vivo degenerating peripheral nerves as of the 4th h after injury. GM-CSF activity was demonstrated by two independent bioassays, and repressed by activity blocking antibodies. Significant levels of GM-CSF were produced by nerve derived fibroblasts, but neither by Schwann cells nor by nerve derived macrophages. Mouse rGM-CSF enhanced MAC-2 production in nerve explants, and up-regulated cell surface expression of MAC-2 by Schwann cells and macrophages. Interleukin-1 beta up-regulated GM-CSF production thus suggesting that injury induced GM-CSF production may be mediated by interleukin-1 beta. Our findings highlight the fact that fibroblasts, by producing GM-CSF and thereby affecting macrophage and Schwann function, play a significant role in the cascade of molecular events and cellular interactions of Wallerian degeneration.

Animals↗
PubMed1992

Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation.

Expression of the macrophage mannose receptor is inhibited by interferon gamma (IFN-gamma), a T helper type 1 (Th-1)-derived lymphokine. Interleukin 4 (IL-4), a Th-2 lymphocyte product, upregulates major histocompatibility class II antigen expression but inhibits inflammatory cytokine production by macrophages. We have studied the effect of IL-4 on expression of the macrophage mannose receptor (MMR) by elicited peritoneal macrophages. We found that recombinant murine IL-4 enhances MMR surface expression (10-fold) and activity (15-fold), as measured by the respective binding and degradation of 125I-mannose-bovine serum albumin. Polymerase chain reaction analysis of cDNAs from purified primary macrophage populations revealed that MMR, but not lysozyme or tumor necrosis factor alpha, mRNA levels were markedly increased by IL-4. The above effects were associated with morphologic changes. These data establish IL-4 as a potent and selective enhancer of murine MMR activity in vitro. IL-4 induces inflammatory macrophages to adopt an alternative activation phenotype, distinct from that induced by IFN-gamma, characterized by a high capacity for endocytic clearance of mannosylated ligands, enhanced (albeit restricted) MHC class II antigen expression, and reduced proinflammatory cytokine secretion.

Animals↗
PubMed2004

Helicobacter pylori infection is associated with increased expression of macrophage migratory inhibitory factor--by epithelial cells, T cells, and macrophages--in gastric mucosa.

The macrophage migratory inhibitory factor (MIF) plays a pivotal role in inflammatory and immune diseases; however, its role in gastrointestinal diseases has not been clarified. This study intended to determine the expression of MIF, by gastric epithelial cells, T cells, and macrophages, in Helicobacter pylori-induced gastritis. Sixty-four patients (30 males, 34 females; mean age, 47 years) referred for upper endoscopy were recruited. Biopsy specimens from the gastric antrum and corpus were obtained for (1) detection of H. pylori and histological examination, (2) single and double immunostaining to test for expression of MIF protein in epithelial cells, T cells, and macrophages, and (2) in situ hybridization for expression of MIF mRNA within the lamina propria. In mucosal specimens from each of the 2 sites, both the percentage of MIF(+) epithelial cells and the numbers of MIF mRNA(+) inflammatory cells, MIF(+) T cells, and MIF(+) macrophages were significantly higher in H. pylori-positive patients than in H. pylori-negative patients. Overall, the percentage of MIF(+) epithelial cells and the numbers of MIF mRNA(+) cells, MIF(+) T cells, and MIF(+) macrophages were higher in the antrum than in the corpus. The percentage of MIF(+) epithelial cells and the numbers of MIF mRNA(+) cells, MIF(+) T cells, and MIF(+) macrophages increased in chronic gastritis, but, in the absence of H. pylori infection, this increase disappeared for all except MIF(+) T cells. Therefore, H. pylori infection is associated with increased expression of the MIF protein and MIF mRNA in gastric epithelial and inflammatory cells; along with other cytokines, MIF may play a significant role in gastric inflammation related to H. pylori infection.

Adolescent↗
PubMed2002

Monocyte chemoattractant protein-1-induced activation of p42/44 MAPK and c-Jun in murine peritoneal macrophages: a potential pathway for macrophage activation.

The role of monocyte chemoattractant protein-1 (MCP-1) in mediating the infiltration and activation of monocytes/macrophages into the sites of inflammation or tumor growth is well documented, but the molecular mechanism(s) involved in the process is poorly understood. In the current investigation, we demonstrate activation of the p42/44 MAPK-mediated signal transduction in murine peritoneal macrophages on stimulation with MCP-1 (10-100 ng/ml) in vitro. The p42/44 MAPK activation was determined by studying the expression of the phosphorylated p42/44 MAPK (Thr202/Tyr204) in the MCP-1-treated macrophages. This response was found to be rapid and time dependent, detectable within 5 min of MCP-1 stimulation. PD98058 (5-50 microM), a specific inhibitor of MAPK kinase (MEK) inhibited the p42/44 MAPK phosphorylation, indicating the specificity of the response. Furthermore, the MCP-1-induced phosphorylation of p42/44 MAPK was found to be blocked by pertussis toxin (100 ng/ml), tyrosine kinase inhibitor-genestein (10 ng/ml), PI3K inhibitor-wortmannin (20-200 microM), and anti-CCR2 antibody (2.5 microg/ml). Additionally, phosphorylation of JNK and activation of the transcription factor, c-Jun, were also noted in response to MCP-1 treatment. Lastly, the MCP1-induced p42/44 MAPK activity was correlated with the functional activation of macrophages by demonstrating the dose-specific inhibition of actin polymerization, macrophage-mediated tumor cell cytotoxicity, and tumor necrosis factor-alpha (TNF-alpha) transcription/production afforded by PD98059 in the MCP-1-treated macrophages. Taken together, these data suggest the involvement of the p42/44 MAPK/c-Jun pathway in the signal transduction process, leading to activation of murine peritoneal macrophages.

Actins↗
PubMed1988

Effect of C-reactive protein on peritoneal macrophages. II. Human C-reactive protein activates peritoneal macrophages of guinea pigs to release superoxide anion in vitro.

The effect of human C-reactive protein (CRP) on macrophage function was studied in an assay of superoxide anion (O2-) production. Peritoneal exudate macrophages (PEM) of guinea pigs exposed in vitro to various doses of CRP for 72 hr resulted in the development of O2- production dose-dependently, measured by increases in superoxide dismutase-inhibitable nitro blue tetrazolium reduction. The O2--producing activity of PEM cultured without CRP, used as a control, decreased markedly in proportion to incubation time. The O2- production by PEM exposed to CRP for 18 hr when control PEM were still high in O2- production, was decreased by larger doses of CRP, while PEM cultured without CRP for 72 hr, when O2- production by control PEM was very low, followed by incubation with CRP for another 18 hr, produced O2- CRP-dose-dependently as in the case of that observed after 72-hr incubation with CRP. These results indicate that CRP is capable of activating macrophages and acts on macrophage function as a modulator. CRP possesses migration inhibitory factor (MIF)-like activity (as reported in the preceding paper) and also macrophage-activating factor (MAF)-like activity, indicating that CRP may play a functional role at the site of inflammation and tissue damage by accumulating and activating macrophages.

Animals↗