Increased Monocyte Production Research Articles

Circulating monocytes decrease significantly following disease-directed therapy and may reflect disease expansion in Langerhans Cell Histiocytosis.

We aimed to examine the association between relative monocytosis and the recurrence of pulmonary Langerhans Cell Histiocytosis. Clinical, laboratory, radiographic and treatment data for 86 patients with a histopathological diagnosis of Langerhans Cell Histiocytosis over a 20-year duration. Parameters such as biological sex, age at diagnosis, time to diagnosis, molecular diagnostic data and imaging were collected. Treatment responses were assessed predominantly through radiography, with RECIST 1.1 criteria applied to MRI or CT scans and PERCIST utilized for serial PET imaging. Investigators also assessed peripheral blood absolute monocyte count at various time points, including initial diagnosis and the most recently available value. While peripheral blood absolute monocyte count between the earliest assessed timepoint and latest value did not differ, the mean value on progression (0.94K/µL), however, was significantly higher than that following re-institution of therapy (0.31, p = 0.000794. Our observation of relative monocytosis on LCH disease progression may be related to an increase in circulating LCH on disease progression or from increased monocyte production for later differentiation into mature dendritic cells that participate in MHC Class 1 upregulation. This trend is especially evident in pulmonary LCH which is incited by tissue trauma and irritation by environmental factors. The phenomena observed in our study parallel other non-LCH cohorts, specifically in published findings from our own group in patients with Rosai Dorfman and Erdheim Chester Disease. To further elucidate the molecular underpinnings of LCH and explore the etiology of this monocyte trend, expanded integrated genomic-transcriptomic sequencing analyses to evaluate the molecular character of LCH and ultimately clarify the origin of this monocyte trend are in progress. These studies are poised to offer invaluable insight to the molecular mechanisms underlying LCH, specifically as they pertain to monocyte signaling and differentiation.

Production of MHCII-expressing classical monocytes increases during aging in mice and humans.

Aging is associated with increased monocyte production and altered monocyte function. Classical monocytes are heterogenous and a shift in their subset composition may underlie some of their apparent functional changes during aging. We have previously shown that mouse granulocyte‐monocyte progenitors (GMPs) produce “neutrophil‐like” monocytes (NeuMo), whereas monocyte‐dendritic cell progenitors (MDPs) produce monocyte‐derived dendritic cell (moDC)‐producing monocytes (DCMo). Here, we demonstrate that classical monocytes from the bone marrow of old male and female mice have higher expression of DCMo signature genes (H2‐Aa, H2‐Ab1, H2‐Eb1, Cd74), and that more classical monocytes express MHCII and CD74 protein. Moreover, we show that bone marrow MDPs and classical monocytes from old mice yield more moDC. We also demonstrate higher expression of Aw112010 in old monocytes and that Aw112010 lncRNA activity regulates MHCII induction in macrophages, which suggests that elevated Aw112010 levels may underlie increased MHCII expression during monocyte aging. Finally, we show that classical monocyte expression of MHCII is also elevated during healthy aging in humans. Thus, aging‐associated changes in monocyte production may underlie altered monocyte function and have implications for aging‐associated disorders.

Increased Monocyte Production of IL-6 after Toll-like Receptor Activation in Children with Autism Spectrum Disorder (ASD) Is Associated with Repetitive and Restricted Behaviors.

The prevalence of autism spectrum disorder (ASD) has starkly increased, instigating research into risk factors for ASD. This research has identified immune risk factors for ASD, along with evidence of immune dysfunction and excess inflammation frequently experienced by autistic individuals. Increased innate inflammatory cytokines, including interleukin (IL)-6, are seen repeatedly in ASD; however, the origin of excess IL-6 in ASD has not been identified. Here we explore specific responses of circulating monocytes from autistic children. We isolated CD14+ monocytes from whole blood and stimulated them for 24 h under three conditions: media alone, lipoteichoic acid to activate TLR2, and lipopolysaccharide to activate TLR4. We then measured secreted cytokine concentrations in cellular supernatant using a human multiplex bead immunoassay. We found that after TLR4 activation, CD14+ monocytes from autistic children produce increased IL-6 compared to monocytes from children with typical development. IL-6 concentration also correlated with worsening restrictive and repetitive behaviors. These findings suggest dysfunctional activation of myeloid cells, and may indicate that other cells of this lineage, including macrophages, and microglia in the brain, might have a similar dysfunction. Further research on myeloid cells in ASD is warranted.

Homozygous Mutations in PHRF1 and PPARG in a Patient with Congenital Neutropenia and Profound Monocytosis: Understanding the Pathway Beyond Monocyte Versus Granulocyte Cell-Fate Choice

Myelopoiesis is a strictly regulated process of monocytes and granulocytes production, originating from common myeloid progenitors. Studies on patients with inherited severe congenital neutropenia (CN) could help to better elucidate myelopoiesis regulation. In CN, maturation arrest of granulocytic precursors at the promyelocytic stage leads to a shift towards monopoiesis and an ineffective granulopoiesis. Hereby we report on a particular CN patient with a typical "maturation arrest" of granulopoiesis at the stage of promyelocytes, very low levels of neutrophils but extremely high levels of monocytes in the peripheral blood and bone marrow. Upon G-CSF treatment (5μg/kg/day) this patient produces high levels of monocytes (up to 24.8x103/μL, more than 50 % of total leukocytes) and only up to 1x103/μl neutrophils. Sanger sequencing of DNA from this patient revealed no mutations in CN-related genes such as ELANE, HAX1 and G6PC3. Therefore we performed whole genome sequencing (Complete Genomics. Inc, Mountain View, CA) of DNA from blood of this patient and his mother to discover causative gene mutations. We identified a homozygous deletion in PHRF1 (PHD and Ring Finger Domain-Containing Protein 1) (p.R1015-G1019, NP_065952.2; rs144630030) and a homozygous missense mutation in PPARG (Peroxisome proliferator-activated receptor gamma) (p.P12A, NP_0569553.2; rs1801282). Both mutations are heterozygote in the patient's mother. Population frequency for heterozygote allele of these two variations was reported to be 13% and 7%, respectively, but no homozygote variants were reported till date. PHRF1 functions as an essential component of the TGF-ß tumour suppressor pathway by triggering degradation of the homeodomain repressor factor TGIF (TG-Interacting Factor) and a consequent retinoic acid signalling activation in haematopoiesis and monopoiesis. PPARG interacts with Retinoid X Receptors (RXR) and controls the expansion of macrophages. In order to evaluate the functional role of the detected mutations on disturbed G-CSF-triggered myelopoiesis in reference CN patient, CD33+ bone marrow myeloid progenitor cells of two healthy controls and this patient were treated with G-CSF in vitro and mRNA expression profiles were analysed in an Affymetrix Microarray platform, followed by Ingenuity Pathway Analysis (IPA). We found, that 'TREM1 signalling' was among the top three pathways with most significant differences (p<9x10-7) between this CN patient and healthy individuals. 'Granulocyte adhesion and diapedesis' and 'LXR/RXR pathway' were the next two significantly affected gene sets (p<8x10-6 and p<1.3x10-5, respectively). TREM1 (Triggering Receptor Expressed on Myeloid cells 1) is a chemokine receptor that is expressed by neutrophils and monocytes, however the ligand that activates this receptor is yet unknown. TREM-1 is involved in neutrophil apoptosis and is known to positively regulate monopoiesis by activation of M-CSF synthesis. Intriguingly, M-CSF was 4.2-fold upregulated in myeloid cells of patient, in comparison to healthy individuals. Other known components of TREM 1 signalling were also among the top 10 differentially expressed genes identified by IPA: HSD11B1 (+20 fold), ATP1B2 (+14 fold) and THBS1 (-10 fold). Functional connections between PPARG and TREM1 is known. PPARG mutation could lead to TREM1 signalling activation that consequently lead to M-CSF over-expression (+4.2 fold). In addition to the activation of TREM1 signalling, deletion in the PHFR1 gene could be the causative effect of marked upregulation of ALDH1A2 (+17 fold), which also could lead to an increase in M-CSF levels and in a retinoid acid signalling activation ultimately leading to increased monocyte production. Together, PPARG and PHRF1 mutations could hyper-activate the secretion of M-CSF by myeloid progenitors leading to a strong shift towards monopoiesis upon G-CSF treatment. Disclosures No relevant conflicts of interest to declare.

Potential Role of Bioactive Lipids in the Development of Non-Antibody Mediated Transfusion-Related Acute Lung Injury (TRALI)

BackgroundTransfusion-related acute lung injury (TRALI) has been the leading cause of transfusion-related morbidity and mortality in the UK and the USA in recent years. A threshold mechanism of TRALI has been proposed in which both patient factors (type and/or severity of clinical insult) and blood product factors (strength and/or concentration of antibodies or biological response modifiers) interact to surpass a threshold for TRALI development (Bux et al. Br J Haematol; 2007; 136: 788-99). The risk of developing antibody-mediated TRALI has been minimised by the introduction of risk-reduction strategies such as limiting the use of plasma from female donors. In contrast, there are no strategies currently in place to mitigate the development of non-antibody mediated TRALI as the mechanisms remain largely undefined. Previous studies have implicated non-polar lipids such as arachidonic acid and various species of hydroxyeicosatetranoic acid (HETE) in the development of non-antibody mediated TRALI (Silliman et al. Transfusion; 2011; 51: 2549-54), however the contribution of these lipids to the development of an inflammatory response in TRALI is poorly understood.MethodologyStandard leucodepleted packed red blood cell (PRBC) units were sampled at either day (D) 2 (n=75) or at D42 (n=113). PRBC-supernatants were obtained via centrifugation, pooled (D2, D42) and levels of arachidonic acid, 5-, 12- and 15-HETE determined using commercial ELISA kits. In an in vitro transfusion model, fresh human whole blood (“recipient”; n=8 for each lipid) was mixed with combinations of culture media (control) or lipopolysaccharide (LPS, 0.23 µg/mL) as a first hit. A range of concentrations of either 5-HETE (200; 1,000; 2,500; 10,000; 250,000 pg/mL), 12-HETE (1,500; 5,000; 62,500; 250,000 pg/mL) or 15-HETE (150; 1,000; 2,000; 8,000 pg/mL) were added as the second hit, and incubated for 6 hours with the addition of a protein transport inhibitor. Neutrophil- and monocyte-specific inflammatory response was assessed using multi-colour flow cytometry (panel: IL-6, IL-8, IL-10, IL-12, IL-1α, IL-1β, TNF-α, MCP-1, IP-10, MIP-1α, MIP-1β). Significance was determined as P < 0.05 by one-way ANOVA with Bonferonni’s correction used to determine dose response (indicated by asterisks).Results5-, 12- and 15-HETE were all detectable in both of the PRBC supernatant pools, with levels increased in D42 compared to D2 (5-HETE: 20,347 vs. 3,449; 12-HETE: 240,967 vs. 1,572; 15-HETE: 7,900 vs. 934; all levels in pg/mL). Arachidonic acid was not detectable in either of the PRBC supernatant pools. In the absence of LPS as a first hit, the addition of non-polar lipids had a predominantly immunosuppressive effect in the transfusion model. 12-HETE suppressed monocyte production of MIP-1α* and neutrophil production of IL-6, IL-8 and IL-12. Also, 15-HETE modulated monocyte IL-8 production and reduced neutrophil production of IL-8, IL-12, IP-10, MIP-1α, MIP-1β and TNF-α. In contrast, in the presence of LPS as a first hit, a predominantly pro-inflammatory response was evident to these lipids. 12-HETE increased monocyte production of IL-1α, IL-8* and MIP-1β* as well as neutrophil production of IL-1α*, IP-10*, MCP-1, MIP-1α* and MIP-1β. In addition, 15-HETE increased neutrophil expression of IL-1α and IL-6, and 5-HETE modulated monocyte production of MIP-1β.ConclusionsThese data suggest that the non-polar lipid mediators investigated here, in particular 12-HETE, may contribute to TRALI pathogenesis. A storage related accumulation of 5-, 12- and 15-HETE was evident in leucodepleted PRBC units. The in vitro model indicated that exposure to these lipid mediators supressed the recipient inflammatory responses in the absence of LPS, but contributed to a pro-inflammatory profile in the presence of LPS as a first hit. Together these data provide further evidence of the importance of both patient (first hit) and blood component (second hit) factors in the development of TRALI. Furthermore, the dose-associated response observed for a number of inflammatory markers is consistent with the threshold hypothesis of TRALI pathogenesis. DisclosuresNo relevant conflicts of interest to declare.

Methotrexate Treatment Causes Early Onset of Disease in a Mouse Model of Ross River Virus-Induced Inflammatory Disease through Increased Monocyte Production

Part of the Togaviridae family, alphaviruses, including chikungunya virus (CHIKV), Sindbis virus (SINV) and Ross River virus (RRV), are able to cause significant inflammatory pathologies ranging from arthritis to encephalitis. Following symptomatic infection with arthritis-associated alphaviruses, patients often experience severe joint pain, affecting distal and small joints, which can last six months or longer. Recently, methotrexate (MTX), a disease modifying anti-rheumatic drug (DMARD), was used to treat patients experiencing chronic rheumatic symptoms following infection with CHIKV. Here, the effect of MTX on Ross River virus disease (RRVD) in mice was examined to better understand its therapeutic potential for alphaviral-induced musculoskeletal disease and to further our knowledge of the development of alphaviral pathologies. Using a mouse model, we analyzed the effect of MTX on RRVD. RRV disease pathogenesis in response to MTX treatment was determined by measuring levels of proinflammatory factors, cellular infiltrates, viral titer and histological analysis of infected tissues. RRV-infected mice receiving MTX treatment rapidly developed musculoskeletal disease, which correlated with a significant influx of inflammatory cell infiltrates into the skeletal muscle tissue. Although no difference was observed in the level of proinflammatory cytokines and chemokines, the viral load increased at early time points post infection in the serum and quadriceps of MTX treated mice, possibly contributing to disease pathogenesis. Results suggest that MTX treatment of acute RRVD in mice provides no therapeutic benefit and underline the importance of inflammatory monocytes in alphaviral induced arthritides.

IFNy Regulates the Balance Between Monocyte and Neutrophil Production During Immune Activation.

AbstractAbstract 1562Recruitment of the appropriate cells from the innate immune system to sites of infection is essential for the defense against pathogens. Depending on the type of invading pathogen, infection induces a rapid release from innate immune cells from the bone marrow, followed by an increased production of those myeloid cells that are most suitable to assist the ensuing immune response in the rapid eradication of the pathogen. However, it is thus far poorly understood what the cellular and molecular mechanism is that underlies this change in hematopoiesis.Using a mouse model with increased numbers of IFNγ-producing T cells in the bone marrow, we have previously found that IFNg plays an important role in the production of myeloid cells and can directly inhibit the formation of eosinophils (De Bruin et al., Blood. 2010 Jun 29). Here we demonstrate that IFNg also skews the balance between monocyte and neutrophil production in the direction of the monocytes. Increased monocyte production was also observed in WT mice infected with LCMV, which was IFNg-dependent, as it was not observed in IFNg-deficient mice. Subsequently, we set out to investigate how IFNγ can modulate the balance between monocyte and neutrophil production. We found that IFNγ reduces the proliferation and differentiation of murine hematopoietic progenitors in vitro in response to G-CSF, while M-CSF responses were not inhibited, but even slightly increased. In addition, IFNγ reduces the capacity of GMPs to form granulocyte colonies in semi-solid cultures and increases their ability to form monocyte/macrophage colonies. On a molecular level, we demonstrate that IFNγ induces a strong upregulation of SOCS3 levels and thereby reduces the phosphorylation of STAT3 in response to G-CSF, thus explaining the reduction in granulocyte formation. The expression levels of M-CSF-R and G-CSF-R by GMPs were not affected by IFNγ, but we found that IFNγ does induce the expression of the monocyte-inducing transcription factors PU.1 and IRF8 in these cells. In conclusion, these data demonstrate that IFNγ can direct myelopoiesis in a lineage-specific manner, thereby modulating the production of the appropriate type of innate immune cells required to combat infection. Disclosures:No relevant conflicts of interest to declare.

Depressed lymphocyte transformation and the role of prostaglandins in atopic dermatitis

We have shown that peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis have a reduced in vitro proliferative responsiveness to concanavalin A when compared with non-atopic controls. Addition of the cyclo-oxygenase inhibitor indomethacin caused a significant enhancement of the mitogen response in the patients, indicating a suppressive effect of cyclooxygenase products. We have further demonstrated increased levels of prostaglandin E2 in the supernatants of the PBMC cultures and increased levels of IgE immune complexes in the sera of the atopic dermatitis patients and therefore hypothesize that IgE immune complexes may cause increased monocyte production of prostaglandins which in turn appears to be responsible for a reduced lymphocyte proliferation.

Stress activation of cellular markers of inflammation in rheumatoid arthritis: Protective effects of tumor necrosis factor α antagonists

Psychological stress is thought to aggravate disease activity in rheumatoid arthritis (RA), although the physiologic mechanisms are unclear. Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine involved in the exacerbation of RA, and TNFalpha antagonists have emerged as efficacious treatments. The purpose of this study was to determine whether RA patients show increased monocyte production of TNFalpha following acute psychological stress and whether such responses are abrogated in RA patients taking TNFalpha antagonists. A standardized stress task was administered to 3 groups of subjects: RA patients taking TNFalpha antagonists, RA patients not taking such medications, and healthy controls. Lipopolysaccharide-stimulated monocyte production of inflammatory cytokines was repeatedly measured using intracellular staining and flow cytometry. Subjective stress, cardiovascular responses, adrenocorticotropic hormone (ACTH) levels, and cortisol levels were also measured. The stress task induced increases in subjective stress, cardiovascular activity, and levels of ACTH and cortisol, with similar responses in the 3 groups. In addition, the stress task induced a significant increase (P < 0.001) in monocyte production of TNFalpha among RA patients who were not taking TNFalpha antagonists. However, monocyte production of TNFalpha did not change following psychological stress in RA patients taking TNFalpha antagonists or in healthy controls. Brief psychological stress can trigger increased stimulated monocyte production of TNFalpha in RA patients. The use of TNFalpha antagonists protects against stress activation of cellular markers of inflammation in RA patients.

Interleukin-6-G-174C polymorphism is associated with occurrence of unstable angina and with in vitro increased monocyte production of interleukin-6 in unstable patients

Interleukin-6-G-174C polymorphism is associated with occurrence of unstable angina and with in vitro increased monocyte production of interleukin-6 in unstable patients

Exogenous melatonin: quantitative enhancement in vivo of cells mediating non-specific immunity

Melatonin (MLT), a biogenic indoleamine and neuromodulator produced by the pineal gland, is known to activate T helper cells by means of direct binding to melatonin receptors on both Th1 and Th2 cells. The present in vivo study aimed to investigate the effect of exogenously administered MLT on the hemopoietic and immune cell populations of the bone marrow and spleen in healthy, young adult male mice at two distinct MLT exposure intervals. The neurohormone, administered daily through the diet (7–14 days), was homogenized into finely ground chow. Control mice received ground chow without MLT. The results revealed cell lineage-specific, quantitative, MLT exposure-time-dependent changes in both the bone marrow and spleen. NK cells and monocytes (both components of the non-specific immune system functioning as the first line of defense against neoplasia and virus infected cells) were significantly increased in the bone marrow by both 7 and 14 days of dietary melatonin. The quantitative increment in these two cell populations, in the organ of their production, i.e. the bone marrow, indicates that new cell proliferation/production may have been stimulated by MLT. In the spleen, as in the bone marrow, NK cell levels remained significantly elevated at both 7 and 14 days after melatonin exposure. However, the number of monocytes in the spleen did not maintain, at day 14 of MLT exposure, the high levels observed after 7 days of MLT, in spite of their sustained, high numbers at 14 days in the bone marrow. This suggests that the progeny of the apparently increased monocyte production in the bone marrow (elevated absolute numbers therein), had localized in anatomical sites (other than the spleen) also common to these cells. Thus, the selective, positive influences of in vivo administered, exogenous melatonin on cells mediating non-specific immunity suggests a plausible mechanism for numerous claims that it is responsible for tumor amelioration in patients.

Roles of factor increasing monocytopoiesis (FIM) and macrophage activation in host resistance to Listeria monocytogenes.

The present contribution concerns two aspects of host resistance in overcoming an infection with Listeria monocytogenes. One of these aspects is the regulation of monocyte production by the factor increasing monocytopoiesis (FIM), a macrophage-derived factor. Listeria-resistant (C57BL/10 mice and Listeria-sensitive CBA mice produce and secrete similar amounts of FIM in response to an inflammation induced by soluble Listeria antigen. However, monocyte precursors in the bone marrow of Listeria-resistant mice react to an injection of serum containing FIM by increased monocyte production, whereas Listeria-sensitive mice are unable to react to this stimulus. The other aspect of host resistance to L. monocytogenes is the activation of macrophages leading to increased bactericidal activity. Macrophages of both mouse strains stimulated first with live BCG and then with PPD, killed ingested Listeria faster than resident peritoneal macrophages did. However, recombinant interferon-gamma, thought to be the most important macrophage-activating factor, did not induce increased listericidal activity in macrophages.

Differences in the response of inbred mouse strains to the factor increasing monocytopoiesis.

Previous studies have shown that monocyte production during an inflammatory response is controlled by the factor increasing monocytopoiesis (FIM), secreted by macrophages at the site of inflammation. The inflammatory reaction to latex particles and a saline-soluble extract of Listeria monocytogenes (SEL), expressed as the number of monocytes in the circulation and of macrophages at the site of inflammation, was about twice as strong in C57BL/10 mice compared with CBA mice. This raised the question as to the mechanism underlying these differences. One possibility might be that these mouse strains differ with respect to the production of FIM, but this cannot be the case because the maximum levels of FIM activity in the serum of both C57BL/10 and CBA mice given latex or SEL intraperitoneally were almost the same; however, the courses of FIM activity in the two strains after intraperitoneal latex were not exactly synchronous. Another possibility is that the sensitivity of monocyte precursor cells for FIM differs. Evidence for the latter was provided by the finding that the intravenous injection of sera with FIM activity obtained from C57BL/10 and from CBA mice into the C57BL/10 mice evoked monocytosis, whereas CBA mice did not respond to these sera. Earlier studies showed that an increase of monocytes after the injection of serum containing FIM reflects increased monocyte production. Taken together, the results of the present study demonstrate that one of the mechanisms underlying the genetic control of the inflammatory response is, rather than enhanced FIM synthesis, the ability of monocyte precursors in the bone marrow to respond to FIM by increased monocyte production.

Quantitative study on the production and kinetics of mononuclear phagocytes during an acute inflammatory reaction.

The present communication concerns a quantitative study on the production and kinetics of mononuclear phagocytes during an acute inflammatory response as compared with the steady-state condition. During an acute inflammation induced by an intraperitoneal injection of NBCS, the peritoneal macrophages increase 2.5 times and there is a concomitant threefold increase of the monocytes in the peripheral blood. This increase of the peritoneal macrophages could be caused by a local proliferation of these cells or by the recruitment of monocytes from the circulation. The results of the in vitro and pulse-labeling studies demonstrate that the mitotic activity of the peritoneal macrophages is not increased during the inflammatory response, which indicates that the increase in the number of these cells is not due to local proliferation. Evidence is also presented that the small proportion (maximally 4%) of peritoneal macrophages that synthesize DNA are very recently arrived from the circulation. In agreement with this is the finding that a small number (less than 3%) of the peripheral blood monocytes are capable of synthesizing DNA. Since proof was obtained that the macrophages in the inflammatory peritoneal exudate originate from peripheral blood monocytes and the number of these cells in the circulation was also augmented, an increased formation of monocytes in the bone marrow was expected. Because increased monocyte production could be brought about by an increased number of promonocytes and/or an acceleration of the mitotic activity of the promonocytes, the various parameters of the cell cycle of these cells were determined. In normal mice the DNA-synthesis time of the promonocytes was 11.8 h, the cell cycle time 16.2 h, and the G(1) + G(2) + M phases 4.4 h. During the first 12 h of the inflammatory response a significantly shorter DNA-synthesis time (7.6 h) and cell cycle time (10.8 h) was found. At 24 h, these values approximated those found in normal mice. Next, both the total production and the rate of production of the monocytes were calculated and compared for both conditions. This computation showed that the total production of labeled monocytes during the first 48 h of an acute inflammation was 64% greater than in normal mice. The rate of production, calculated in two ways (i.e., from the data of the total production and also from the data of the cell cycle time together with the total number of promonocytes) complemented each other very well. During the first 12 h of the inflammatory response the production rate was increased 1.5 times and then leveled off, reaching almost the normal rate after 24 h. Furthermore, the excellent agreement between the results of the two methods of calculation for the normal steady state confirmed once more that the promonocyte is the direct precursor cell of the monocyte, giving rise to the two monocytes after each division. The kinetics of the monocytes in the peripheral blood was also altered during the inflammatory response. During the first 48 h, twice the normal number of labeled monocytes went from the bone marrow to the peripheral blood and twice the normal number also left the circulation. Furthermore, at least 70% of this increased number of labeled monocytes leaving the circulation migrated into the inflammatory exudate of the peritoneal cavity, leading to a roughly 11-fold increase of labeled peritoneal macrophages.