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PubMed1993

Phagocytosis of Mycobacterium tuberculosis or particulate stimuli by human monocytic cells induces equivalent monocyte chemotactic protein-1 gene expression.

Phagocytosis of Mycobacterium tuberculosis by human monocytes or macrophages is classically followed by granuloma formation in vivo. Granuloma are comprised of cells of the monocyte lineage together, in many instances, with antigen-specific T lymphocytes. Development of granuloma depends upon recruitment of both cell types, but recruitment of monocytes is pivotal as these cells secrete anti-mycobacterial cytokines and IL-8, a T cell chemoattractant. We have therefore investigated gene regulation of Monocyte Chemotactic Protein 1 (MCP-1), an important monocyte chemotactic cytokine, following phagocytosis of particulate material (latex beads and zymosan) and live M. tuberculosis by two human monocytic cell lines. In THP-1 cells and phenotypically more differentiated Mono Mac 6 cells, MCP-1 mRNA accumulation was first detectable by Northern analysis of 4 hours and increased over 24 hours. Magnitude and kinetics of MCP-1 gene expression was independent of the biochemical nature of the phagocytic stimulus, M. tuberculosis strain virulence or pre-treatment with anti-TNF. In contrast to the uniform effect of different phagocytic stimuli on MCP-1 gene expression, we have shown that M. tuberculosis but not latex or zymosan, increased IL-8 gene expression, a chemotactic agent for T cells. In additional experiments with THP-1 cells infected with human immunodeficiency virus (HIV), viral infection did not alter MCP-1 gene expression following phagocytosis. MCP-1 gene expression appears to be a conserved antigen-independent response of human monocytic cells which is activated following particulate phagocytosis. MCP-1 gene expression may thus be involved in recruitment of monocytes during granuloma formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Line↗

PubMed1981

The metabolism of native and malondialdehyde-altered low density lipoproteins by human monocyte-macrophages.

We have recently shown that cultured human monocyte-macrophages degraded 125I-labeled low density lipoprotein (125I-nativeee-LDL) by a saturable high-affinity process with maximal velocity at 25-30 microgram protein/ml (Fogelman et al., 1980, Proc. Nat. Acad. Sci. USA. 77:2214-2218). We now describe studies of the binding of 125I-native-LDL at 4 degrees C and the effects of chloroquine, Ca2+ concentration, and reductive methylation on high-affinity 125I-native-LDL degradation that indicate that native-LDL is processed by the monocyte-macrophages via the classic LDL receptor pathway. The high-affinity degradation of 125I-native-LDL increased substantially when monocyte-macrophages were exposed to the lipoprotein deficient-fraction of serum (LPDS) for periods as brief as 4 hours, and was 25-fold greater than that of lymphocytes. Freshly isolated monocytes that had never been exposed to LPDS also demonstrated high-affinity degradation of 125I-nativ-LDL. When these monocytes were cultured for 7 days in a medium containing native-LDL at a concentration (186 microgram protein/ml) greatly in excess of that apparently needed to saturate the high-affinity process, there was more than a 10-fold increase in 125I-native-LDL high-affinity degradation. LDL modified by treatment with malondialdehyde was processed by a second high-affinity cell surface receptor that appears identical to the "scavenger" receptor that processes acetylated LDL (Goldstein, et al., 1979, Proc. Nat. Acad. Sci. USA. 76: 333-337).

Cells, Cultured↗

PubMed2004

Infection-induced modulation of m1 and m2 phenotypes in circulating monocytes: role in immune monitoring and early prognosis of sepsis.

To monitor and better understand the immunoinflammatory sequelae in sepsis and septic shock, systemic and monocyte-related cytokine responses were evaluated in baboons with experimental peritonitis induced by an E. coli-laden fibrin clot. Despite similar bacterial inocula, considerable interindividual variability in clinical manifestation and outcome of infection was observed. Because monocytes and macrophages are a key component of innate immunity, we hypothesized that early polarization of distinct activation programs in circulating monocytes that culminates in the emergence of either classically (M1) or alternatively (M2) activated monocytes may underlie the observed susceptibility or resistance to infection. To test our hypothesis, we analyzed infection-induced expression of cytokine mRNAs in monocytes isolated from surviving and dead animals. Our data show that resistance to E. coli sepsis may well be associated with a mixed M1/M2 activation state of circulating monocytes, whereas M1 phenotype appeared to be prevailing in monocytes from animals that died. Together with data on systemic cytokine responses, the latter findings indicate that morbidity and mortality of animals with gram-negative sepsis may well result from an overwhelming proinflammatory response. Collectively, our data contribute to a better understanding of cytokine networking in the immunoinflammatory response to microbial infection and suggest M1/M2 immunophenotypic profiling of readily available circulatory monocytes for early prognosis of severe infections.

Animals↗

PubMed2002

Regulatory effects of deoxycholic acid, a component of the anti-inflammatory traditional Chinese medicine Niuhuang, on human leukocyte response to chemoattractants.

Niuhuang is a commonly used Chinese traditional medicine with immunoregulatory and anti-inflammatory properties. Deoxycholic acid (DCA) is a major active constituent of Niuhuang. The reaction of human leukocytes to chemoattractants is an important part of the host immune response and also plays a crucial role in the development of inflammation. We, therefore, investigated the in vitro effects of DCA on human monocyte and neutrophil responses to classic chemoattractants [fMet-Leu-Phe (fMLP), complement fraction 5a (C5a)], CC chemokine [monocyte chemoattractant protein-1 (MCP-1/CCL2)], and/or CXC chemokines [stromal cell-derived factor-1 (SDF-1alpha/CXCL12), interleukin-8 (IL-8/CXCL8)]. The results showed that DCA significantly inhibited fMLP-induced monocyte and neutrophil chemotaxis and calcium mobilization, and also blocked the binding of [3H]fMLP and anti-formyl peptide receptor (FPR) monoclonal antibodies (mAb) to the cells. The inhibitory effects of DCA on calcium mobilization and anti-FPR-mAb binding to the receptor could be abrogated by washing DCA out of the cell suspension, suggesting that DCA blocked fMLP receptors via a steric hindrance mechanism, not via receptor internalization. DCA had no significant inhibitory effects on MCP-1-, SDF-1alpha-, or C5a-induced monocyte function, or C5a- or IL-8-induced neutrophil function. Taken together, our experimental results suggest that blockade of fMLP receptors may contribute to the anti-inflammatory effects of traditional medicine containing DCA.

Anti-Inflammatory Agents↗

PubMed1992

IL-4 enhances programmed cell death (apoptosis) in stimulated human monocytes.

Because IL-4 down-regulates several proinflammatory functions associated with human monocytes/macrophages, we explored the possibility that IL-4 also decreases monocyte survival. IL-4 caused a concentration-dependent decrease in viability of IL-1 or LPS stimulated, but not unstimulated, monocytes. Nonviable cells demonstrated classic features of programmed cell death or apoptosis, in that they were condensed and contained oligonucleosome-sized (200 bp) DNA fragments. When compared with several other cytokines commonly associated with inflammatory lesions, IL-4 was uniquely effective in enhancing cell death. We found that IL-4 enhanced death more quickly in IL-1-stimulated cells than in LPS-stimulated cells, that stimulated monocytes did not become resistant to the effects of IL-4 during culture, and that the effects of IL-4 on viability were antagonized by IFN-gamma. Enhanced cell death was stimulus-specific in that monocyte viability maintained by certain activating agents, such as Con A or CSF, was unaffected by IL-4. These findings represent the first evidence of cytokine-enhanced programmed cell death in monocytes and suggest that the antiinflammatory effects of IL-4 are mediated in part by reducing survival of stimulated monocytes in chronic lesions.

Cell Death↗

PubMed2000

Cell contact-mediated signaling of monocytes by stimulated T cells: a major pathway for cytokine induction.

T lymphocytes are currently thought to play a pivotal part in the pathogenesis of chronic inflammatory diseases. However, the mechanism(s) by which they exert their pathogenic effect remain(s) elusive. Contact-mediated signaling of monocytes by stimulated T cells is a potent pro-inflammatory mechanism that triggers massive up-regulation of the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-alpha) that play an important part in chronic destructive diseases such as rheumatoid arthritis and multiple sclerosis. To date cell-cell contact is the only endogenous mechanism to be described that displays such an activity in monocyte-macrophages which are classically stimulated in vitro by bacterial products such as LPS or non-specific stimuli such as phorbol esters or poorly activated by soluble cytokines such as IFN-gamma. Since direct cellular contact occurs at the inflammatory site, we hypothesized that this mechanism is relevant to the pathogenesis of chronic inflammatory disorders. This review aims at summarizing the state of the art and importance of contact-mediated monocyte activation by stimulated T lymphocytes.

Animals↗

PubMed1987

The spontaneous ability of normal human IgG to inhibit the Fc receptors of normal human monocytes is related to their binding capacity to lectins.

The lectin-binding capacity of 96 normal human IgG, assessed by solid-phase radioimmunoassay, strikingly varied according to the lectin considered. Indeed, half of the IgG samples exhibited peanut agglutinin (PNA)- and pokeweed mitogen-specific binding capacities superior or equal to 4%, whereas less than 15% of IgG similarly bound to concanavalin A (Con A) and to phytohemagglutinin. The ability of those IgG to inhibit the Fc receptor (Fc-R) function of human monocytes, measured by a classical rosette assay, was inversely correlated to their binding ratios to PNA and Con A only. By affinity chromatography, three groups of IgG were separated: the IgG purified on agarose-PNA columns slightly reduced the Fc-R function (40-45% inhibition); the IgG purified on Sepharose-Con A columns exhibited the highest inhibitory properties (80-85% inhibition); the IgG that did not bind to PNA and Con A columns possessed intermediate inhibitory properties (65-70% inhibition). The different effect of IgG on Fc receptors was conserved when monocytes were first treated by trypsin and was unrelated to their specific binding to human monocytes, to their subclasses, and to their C1q- or protein A-binding capacities. Incubation of monocytes with D-galactose (10 mM) significantly improved their capacity to form IgG rosettes, whereas their incubation with D-mannose (10 mM) significantly reduced the Fc-R function. Scatchard plots of 125I-IgG1 myeloma protein binding to monocytes were linear under basal conditions, as well as after a prior incubation of the cells with D-galactose or D-mannose. Monocytes bound about 16,000 molecules of IgG1 per cell in each instance. In contrast, the mean association constant (Ka) for IgG1 binding was 2.59 +/- 0.50 X 10(8) M-1 under basal conditions, 4.4 +/- 0.75 X 10(8) M-1 after D-galactose incubation, and 1.35 +/- 0.50 X 10(8) M-1 after D-mannose incubation. These data suggest that the level of human monocyte Fc-R function blockade induced by human IgG depends mainly on the presence of "accessible" galactosyl or mannosyl residues in the Fc domain and that the modulation of the Fc-R function induced by these carbohydrates is due to a change in the affinity rather than in the number of single class of high-affinity binding sites.

Chromatography, Affinity↗

PubMed1977

The migrant cells in allotransplants of heart, kidney and skin. II. Monocyte-macrophage activity.

Within a few hours of transplantation the cells of the mononuclear phagocyte system migrate into the interstitial tissues of the organ. The cells arrive on the vascular endothelium of the allotransplanted organ either as macrophages or as monocytes but on entering the interstitial tissues they begin to enlarge, differentiate and undergo active pinocytosis. Along with the cell migration, which would appear to be their stimulus to migrate, is an extravasation of the protein-rich plasma. Erythrocytes also pass into the interstitium and, if effete, are contracted by monocyte-macrophages and phagocytosed in the classical manner. All through the natural history of an allotransplant new monocyte-macrophage recruits arrive the interstitial tissues of the allotransplant. Some of these cells escape via the lymphatics but the vast majority accumulate in the allotransplant, interdigitate and fuse with one another but make no attempt to damage the tissues into which they have migrated. The reaction to an allotransplanted organ fits into the category of an aseptic inflammatory reaction and the only obvious role played by the mononuclear phagocyte system is the classical role of scavenging interstitial debris.

Animals↗

PubMed2006

Increased expression of monocytic angiotensin-converting enzyme in dialysis patients with cardiovascular disease.

BACKGROUND: Patients with chronic renal disease suffer from accelerated atherogenesis, which is promoted by inflammation and oxidative stress. Tissue angiotensin converting enzyme (ACE) exerts proinflammatory and prooxidative effects by producing angiotensin II. Monocytes are strongly involved in the pathogenesis of atherosclerosis. They express ACE, which might contribute to their atherogenic potency. We hypothesize that dialysis patients have increased monocytic ACE expression, and that ACE expression on circulating monocytes is associated with prevalent cardiovascular disease. METHODS: In 74 dialysis patients, ACE expression on total monocytes and monocyte subsets was measured flow-cytometrically in a whole-blood assay. A subpopulation of 22 dialysis patients was compared to an age- and gender-matched control group with intact renal function. Cardiovascular risk factors and the prevalence of cardiovascular disease were assessed. In a subgroup of patients (n = 8), monocytic ACE activity was measured in vitro and correlated with monocytic ACE expression. RESULTS: Dialysis patients had an increased expression of monocytic ACE compared to controls. Monocytic ACE expression was higher in dialysis patients with prevalent cardiovascular disease than in those without cardiovascular disease. This association remained significant after correction for classical cardiovascular risk factors. Among monocyte subsets, CD14++CD16+ monocytes had the highest ACE expression. Monocytic ACE activity correlated with ACE surface expression. CONCLUSIONS: The finding of increased ACE expression on monocytes of dialysis patients with cardiovascular disease links monocytes to the activated renin-angiotensin system. ACE expression was found highest among CD14++16+ monocytes, which is in accordance with a prominent role of these proinflammatory cells in atherogenesis.

Aged↗

PubMed2004

Comparison of in vitro-activity of commonly used topical glucocorticoids on cytokine- and phospholipase inhibition.

BACKGROUND AND OBJECTIVES: Topical glucocorticoids (GCs) are potent inhibitors of cellular inflammatory mediator production. Differences in receptor binding activities are believed to correlate with inhibition of mediator release and anti-inflammatory efficacy in vivo. To further assess this hypothesis we compared in cultured human monocytes the inhibitory activity of classic synthetic GCs on leukotriene B4 (LTB4), prostaglandin E2 (PGE2), interleukin 1 beta (IL-1beta) and c-phospholipase A 2 activity (cPLA2). METHODS: Normal human monocytes (10(5) /ml) were tested for 20 hrs with increasing concentrations (range 10(-12) -10(-5) M) of triamcinolone acetonide (TAA) compared to beclomethasone dipropionate (BDP), budesonide (BUD), dexamethasone (DEX), or the ethanol diluent together with 10 microg/ml of lipopolysaccharide (LPS). Mediator production and spontaneous cPLA subset 2-activity was determined by direct enzyme immunoassay methods. RESULTS: TAA at therapeutically relevant concentration (10(-8) M) inhibited significantly (p<0.01, n = 9) mediator production of TNF-alpha > IL-1beta > TxB2 > LTB subset 4 in a dose dependent manner by 75%, 65%, 41%, and 33%. IL-1beta inhibition at 10(-8) M by TAA (65%)> BDP (52%)> BUD (47%) was not different (ANOVA, p>0.2). Also spontaneous cPLA2-activity at 10(-8) M was inhibited to a similar degree (ANOVA, p> 0.6) by BUD (17.3%) > TAA (11.4%) > BDP (8.6%). In the same culture conditions spontaneous PGE2-secretion was inhibited by BDP (28.8%) > BUD (24.2%) > TAA (11.4%) with no significant effect for TAA. CONCLUSION: Clinically well established GCs have a similar inhibitory capacity on monocyte cytokine production and surprisingly only weak effects on AA-metabolism. Small receptor binding activity may account for the lack of cytokine inhibition by subtherapeutic (<10(-8) M) airway concentrations of TAA and BDP. Partial mediator inhibition by GCs at therapeutically known airway concentrations may be relevant to control bursts of airway inflammation during acute exacerbation but unfavourable to effectively delay progression of chronic airway inflammation.

Administration, Cutaneous↗

PubMed1999

Classical swine fever virus in plasma and peripheral blood mononuclear cells of acutely infected swine.

The distribution of classical swine fever virus (CSFV) in plasma, monocytes, T and B lymphocytes in peripheral blood was monitored during experimentally induced acute classical swine fever infection in piglets. Six piglets were infected with 10(3.8) TCID50 of virus and blood samples taken up to 18 days post-inoculation (p.i.). Infectious virus was detected in monocytes, T and B lymphocytes to similar titres in five of the six infected piglets. Infectious virus was detected earlier in plasma than in any of the mononuclear cell subpopulations. No significant difference was observed in the period of time in which virus could be isolated from the three cell subpopulations. While a progressive lymphopenia developed, a marked B cell depletion was observed. However, B cells were apparently replaced by non-IgM-bearing mononuclear cells, as the proportion 'total lymphocyte/total leucocytes' remained unaltered throughout the experiment. Virus titres in plasma and peripheral blood mononuclear cells showed a tendency to increase as the disease progressed to its outcome.

Acute Disease↗

PubMed1993

'Classic' anti-neutrophil cytoplasmic autoantibodies (cANCA), 'Wegener's autoantigen' and their immunopathogenic role in Wegener's granulomatosis.

Wegener's autoantigen (WA), a 29 kD multifunctional protein, is the principal target antigen of autoantibodies associated with Wegener's granulomatosis (WG). WA was first identified as proteinase 3 (PR3), which is now known to be identical with myeloblastin and AGP7. Like other lysosomal proteins, WA/PR3 displays enzymatic activity, differentiation factor activity for myeloid precursor cells, and antimicrobial functions. Neutrophilic polymorphonuclear leukocytes (PMN) and a subpopulation of monocytes contain high levels of WA/PR3 in their myeloperoxidase-positive granules. The autoantibodies from WG sera produce a finely granular, centrally accentuated fluorescence pattern on PMN and monocytes and have been designated 'classic' pattern antineutrophil cytoplasmic autoantibodies (cANCA). However, PMN/monocyte activation (in vitro/ex vivo) is associated with the translocation of WA/PR3 on the cytoplasm membrane. WA/PR3 is accessible to the WG-associated autoantibody: cANCA stimulate cytokine-preactivated PMN to produce oxygen radicals and to degranulate. Furthermore, cANCA interfere with the biological functions of WA/PR3 (e.g. inhibition of elastinolytic activity). Hence, cANCA represents not only the best seromarker for WG so far available, but several lines of evidence indicate that the autoantibodies against WA/PR3 play a major role in the pathogenesis of this enigmatic disease.

Amino Acid Sequence↗

PubMed1989

Naloxone-reversible monocyte dysfunction in patients with chronic fatigue syndrome.

We studied monocyte function in 35 consecutive patients with chronic fatigue syndrome (CFS) and 25 healthy controls. Eighty-five per cent of the patients showed monocyte dysfunction characterized by marked reduction in the number of monocytes displaying immunoreactive cytoskeletal vimentin filaments, a low phagocytosis index, and a reduced expression of HLA-DR antigens. These values increased dramatically after incubation of the patients' monocytes with the opioid antagonist naloxone. Other immunological abnormalities also noted in the patients were low lymphocyte blastogenesis and diminished numbers of monocytes displaying receptors for Fc of IgG (FcR) and C3b (CR1). These findings suggest that an increased opioid activity acting through a classical receptor mechanism is active on monocytes from a high proportion of patients with CFS and that this represents a novel example of immunomodulation by opioid peptides in human disease. We suggest that endogenous opioids are involved in the pathogenesis of the chronic fatigue syndrome.

Adult↗

PubMed1997

Induction of stress proteins by tobacco smoke in human monocytes: modulation by antioxidants.

Tobacco smoke (TS) induced in human monocytes the synthesis of both the classical heat shock proteins (HSP) (Hsp70, Hsp90, Hsp110) and the oxidation-specific stress protein (SP) heme oxygenase (HO). To determine the role of reactive oxygen species in SP induction by TS, we incubated the monocytes with various antioxidants before exposure to TS. Quercetin and N-acetylcysteine (NAC) both prevented the induction of HO by TS but not, or less so, than that of the classical HSP, while the nitric oxide synthase inhibitor L-nitroarginine had no effect. Thus, at least two mechanisms appear involved in SP induction by TS; (i) the induction of HO (oxidation-dependent), which was prevented by quercetin and NAC; and (ii) the induction of Hsp70, which was, at least in part, oxidation-independent. SP induction might represent an adequate biosensor for TS and other radical-mediated environmental exposures.

Adult↗

PubMed1990

T-cell-induced expression of human immunodeficiency virus in macrophages.

Macrophages are major reservoirs of human immunodeficiency virus (HIV) in the tissues of infected humans. As monocytes in the peripheral blood do not show high levels of infection, we have investigated the expression of HIV in T-cell-activated, differentiated macrophages. Peripheral blood mononuclear cells were isolated from HIV-seropositive individuals and stimulated with antigens or mitogens, and the nonadherent fraction was removed. Macrophages were cultured alone for 2 weeks, and HIV expression was assessed. Results from p24 antigen capture assays demonstrated that the presence of autologous T cells and concanavalin A or autologous T cells and allogeneic cells for the initial 24 h of culture induced HIV expression in 35 of 47 (74%) HIV-seropositive patients tested. The macrophage monolayers could be immunostained with anti-HIV antibodies to reveal discrete infectious centers, indicating that complete virus replication was occurring in the macrophages and that infection of adjacent cells was mediated by cell-cell contact. Time course studies of the interval of coculture of the adherent and nonadherent cells indicated that 24 h (but not 2 h) was sufficient for induction of HIV in the macrophages. Direct contact between the adherent cells and activated T cells was required as well. Since the presence of autologous T cells also appeared to be necessary, induction of HIV expression in macrophages may be genetically restricted. HIV-seronegative nonadherent cells were able to induce HIV expression in macrophages from HIV-seropositive donors, demonstrating that the virus originated in the monocytes and was reactivated in the context of a classic T-cell-mediated immune reaction. The high percentage of monocytes from HIV-seropositive donors which can be induced to replicate HIV by activated T cells suggests that infection of monocytes may be critical to the pathogenesis of this lentivirus infection.

Cell Communication↗

PubMed1988

T6 positive cells in the peripheral blood of burn patients: are they Langerhans cells precursors?

Peripheral blood mononuclear cells of 14 patients suffering thermal injury were separated by affinity chromatography on peanut agglutinin (PNA) coupled to Sepharose macrobeads. The resulting PNA positive subset was 14% of the total mononuclear population. About 30% of these cells were found to coexpress T6(CD1), Ia-like and the myeloid differentiation antigens My4(CDw14) and Mo1(CD11). In comparison, the PNA+ subset from normal blood donors (about 5% of total mononuclear cells) contained mature monocytes that were found to be T6 negative. Electron microscopic studies using immunogold labeling showed that the T6 positive cells were slightly smaller than monocytes but larger than the classical lymphocytes and had common morphologic features with the Langerhans cells of the skin. Considering that patients suffering extensive damage of the epidermis require fast renewal of all skin elements, it is possible that the cells we identified in their peripheral blood are the precursors of the Langerhans cells of the skin en route from bone marrow to the epidermis.

Adolescent↗

PubMed2006

At least one YMHCI molecule in the chicken is alloimmunogenic and dynamically expressed on spleen cells during development.

Transcriptionally active, MHC class I (MHCI) loci are located in two separate polymorphic genomic regions in the chicken called B and Y. The YMHCI gene sequences encode molecules with uncommon substitutions in the antigen-binding region indicating that YMHCI molecules are likely unique and may bind a specialized form of antigen distinct from that of other antigen-binding MHCI molecules. To learn whether YMHCI gene expression results in the production of alloantigens at the cell surface, we immunized 15I(5) x 7(2) : chickens using syngeneic RP9 cells expressing transduced YF1w*7.1, a potentially alloimmunogenic YMHCI allele from the Y7 haplotype present in line C. The resulting antisera show that YF1w*7.1 MHCI molecules are immunogenic and expressed on the surfaces of cells in blood and spleen of line C chickens. Virtually all CD3+, CD4+, and CD8+ cells circulating in line C blood are positive, as are BU1+ cells. The YF1w*7.1 MHCI allele is dynamically expressed at levels comparable to but transcriptionally independent of classical BMHCI on erythrocytes, lymphocytes, granulocytes, monocytes, and thrombocytes within the spleen pre- and post-hatching. The antisera react with cells from two among four haplotypes segregating in closed populations of lines N and P. YMHCI shares features associated with both classical and non-classical MHCI. It is becoming increasingly likely that YMHCI has a fundamental role in avian immunity and thereby needs to be included in the growing spectrum of functionally active, diverse MHCI molecules no longer adequately described by the classical/non-classical dichotomy.

Animals↗

PubMed1987

Interferon-gamma is a major regulator of C1-inhibitor synthesis by human blood monocytes.

C1 inhibitor (C1INH) is the major control factor for the activation of the classical pathway of complement and for contact system activation. Hepatocytes and blood monocytes are known to synthesize this protease inhibitor. We studied the regulation of monocyte C1INH production by mediators that are generated during inflammatory responses. Purified blood monocytes spontaneously synthesized and secreted C1INH only after prolonged culture. In the presence of interferon (IFN)-gamma, C1INH was detectable within 24 hr and continued to be released at high levels throughout an 8-day culture period. Monocyte C1INH was newly synthesized and was functionally active as determined by forming stable complex with C1s. Other monocyte stimuli were either less potent (IFN-alpha, IFN-beta) or not capable of increasing C1INH release (lipopolysaccharide, interleukin 1, and tumor necrosis factor). The second component of complement, C2, was induced by IFN-gamma to a similar extent as C1INH. These findings demonstrate that IFN-gamma is a major regulator of monocyte C1INH production and may warrant consideration of IFN-gamma in the treatment of C1INH deficiency states.

Cells, Cultured↗