SEARCH · PubMed Health

Results for “classical monocytes”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 775 records · Page 43Linked to original sources

PubMed1998

IFN-gamma induces the high-affinity Fc receptor I for IgG (CD64) on human glomerular mesangial cells.

The deposition of immune complexes, followed by activation of complement and/or Fc receptors and generation of chemoattractants, is the most common feature of human glomerulonephritis. Recently we have shown that primary cultured human glomerular mesangial cells (HMC), which are normally negative for IgG Fc receptors, can be stimulated to express the low-affinity FcgammaRIII-A receptor isoform. In this study we further demonstrate that activation of HMC through IFN-gamma resulted in the functional expression of the high-affinity Fc receptor for IgG (FcgammaRI, CD64). IFN-gamma-dependent induction of classical FcgammaRIa1 mRNA as well as a2, b2 splice variants were evident after 24 h in proliferating HMC and after 48 h in resting HMC. Transcription of FcgammaRI mRNA was also induced by IL-10 in proliferating HMC, whereas other cytokines such as IL-3, transforming growth factor-beta1 and granulocyte-macrophage colony-stimulating factor were not effective. Cell surface expression of FcgammaRI could be detected by flow cytometric analysis after IFN-gamma stimulation and was accompanied by the augmentation of MHC class II and the up-regulation of intercellular adhesion molecule-1 expression. Triggering of HMC by cross-linking FcgammaRI with F(ab')2 fragments of the anti-CD64 monoclonal antibody 22 led to enhanced synthesis of mRNA for the chemokines IL-8 and monocyte chemoattractant protein-1, indicating that the FcgammaRI of HMC is functionally active. These in vitro data suggest that engagement of both FcgammaRI and FcgammaRIII-A on activated HMC through IgG immune complexes may result in an increased chemoattraction of leukocytes into the glomerulus, contributing to the development of glomerulonephritis.

Cells, Cultured↗

PubMed1994

Occurrences, specificities, and functions of ubiquitous antibodies in human serum that are reactive with the Cryptococcus neoformans cell wall.

Previous studies found that normal human serum (NHS) contains an immunoglobulin G (IgG) antibody that mediates initiation of the classical complement pathway by nonencapsulated Cryptococcus neoformans. The present study used an enzyme-linked immunosorbent assay with whole nonencapsulated yeast cells as solid-phase antigens to demonstrate the presence of high levels of IgG antibody in each of 11 sera from normal adult donors. The IgG antibodies were of the IgG2 subclass. The antibody activity was blocked completely by treatment of serum with isolated yeast glucan. Treatment of serum with mannan or chitin had no effect on antibody levels. Antibody activity was adsorbed completely by treatment of serum with zymosan particles. Adsorption with intact cells of Saccharomyces cerevisiae or Candida albicans had no effect, suggesting that the glucan on S. cerevisiae or C. albicans is not surface exposed. Assessment of the opsonic requirements for phagocytosis of nonencapsulated cryptococci by monocyte-derived human macrophages (MO-M phi) showed that high levels of phagocytosis occurred when yeast cells were opsonized with NHS. Removal of anti-glucan antibody by adsorption with whole nonencapsulated cryptococci did not diminish opsonic activity. Heat-inactivated serum or anti-glucan antibody affinity purified from NHS lacked opsonic activity. Taken together, these results indicate that phagocytosis of nonencapsulated cryptococci by monocyte-derived human macrophages has an obligatory requirement for opsonic ligands of the complement system, with no contribution by the anti-glucan IgG that is found in NHS.

Antibodies, Fungal↗

PubMed2000

Reaction patterns of monoclonal antibodies to HLA-G in human tissues and on cell lines: a comparative study.

We compared the immunohistochemical reaction patterns of HLA-G-specific antibodies 87G, 4H84, G233, 16G1, and BFL.1 on human placentas under three different preparative conditions and on cryosections of other human tissues. Human and murine cell lines, either naturally expressing or transfected with HLA-G, were analyzed for their reaction patterns by immunocytochemistry and flow cytometry. Antibodies HCA2, TP25.99, W6/32 to classical HLA class I, anti-beta(2)-m and various non-HLA-G expressing cell lines were used as controls. The binding ability of the antibodies depends on the histotechnical procedure used. 4H84 and HCA2 bind to HLA-G despite aldehyde fixation and also paraffin embedding. 87G does not bind HLA-G in studies involving fixation with aldehydes. G233 labels HLA-G in aldehyde fixed but not paraffin embedded tissues. By immunocytochemistry HLA-G2 is merely detected with antibodies 4H84 and HCA2. MAb 16G1 binds to HLA-Gsol transfected cell lines only. The HLA-G specificity of mAb BFL.1 was considered as doubtful because it failed to react with most of the HLA-G transfected cell lines. Binding of 87G to the surface of monocytes or U-937 cells stimulated with IFN-gamma and GM-CSF is an Fc-receptor mediated phenomenon.

Animals↗

PubMed2004

mRNA expression of nuclear receptor RZR/RORalpha, melatonin membrane receptor MT, and hydroxindole-O-methyltransferase in different populations of human immune cells.

We characterized the expression levels of the retinoid Z receptor alpha (RZR alpha), RORalpha mRNA isoforms (RORalpha1, RORalpha2, and RORalpha3), and both melatonin receptor MT1 and hydroxindole-O-methyltransferase (HIOMT) genes. For this purpose, the following human peripheral blood mononuclear cells populations were isolated: monocytes (CD14+ cells), B lymphocytes (CD19+ cells), T helper lymphocytes (CD14(-) CD4+), cytotoxic T lymphocytes (CD56(-) CD8+ cells), and natural killer (NK) lymphocytes (CD56+ cells). PBMCs subsets were obtained by Dynabeads M-450 (Dynal) isolation procedure. We observed a strong gene expression signal for RZRalpha in all subpopulations studied, whereas both RORalpha1 and RORalpha2 transcripts were amplified only in CD8+ cells. Specific signal for RORalpha2 was obtained in all subpopulations studied, but we were not able to detect the RORalpha3 mRNA transcript in human immune cells studied. A weaker signal (especially in CD19+ cells) was also detected in all subsets of cells for the MT1 gene. With regard to HIOMT, a strong signal was achieved among all but one subpopulation of cells; the only exception was CD14+ cells. Thus, in addition to its classical function in the nervous and endocrine system, melatonin could act directly as a paracrine and/or autocrine agent in the human immune system.

Acetylserotonin O-Methyltransferase↗

PubMed2000

Circulating cytokines as mediators of fever.

The febrile response is thought to be mediated by endogenous mediators, generically called "endogenous pyrogens." In the classical model of pathogenesis, induction of fever is mediated by the release of pyrogenic cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and interferons into the bloodstream in response to exogenous pyrogens. These mediators act at the level of the organum vasculosum of the lamina terminalis in the central nervous system (CNS), inducing synthesis of prostaglandins, which are the central mediators of the coordinated responses leading to fever. However, analysis of recent data suggests that multiple pathways may be involved in the induction of fever by cytokines, such as local cytokine production leading to signaling through vagal fibers, release of cytokine-induced circulating mediators at the tissue level, the use of membrane-bound cytokines as mediators, or the local release of cytokines in the hypothalamus by circulating activated monocytes. In addition, certain bacterial products can stimulate cytokine production directly at the level of hypothalamus, probably by activation of Toll-like receptors. A multipathway mechanism for the induction of fever is therefore suggested.

Central Nervous System↗

PubMed2006

C-type lectin-like receptors on myeloid cells.

Host defence against pathogens requires the recognition of conserved microbial molecules, or 'pathogen-associated molecular patterns' (PAMPs), by their receptors termed 'pattern recognition receptors' (PRRs), represented most notably by toll-like receptors (TLRs) and C-type lectins. The 'non-classical' C-type lectins (these that lack the residues involved in calcium binding, required for carbohydrate binding) are traditionally thought of as being restricted to natural killer (NK) or T cells, playing important roles in immune surveillance. In recent years, however, a growing number of these receptors have been identified on myeloid cells, both of human and mouse origin. In contrast to their NK counterparts that primarily control cellular activation through recognition of major histocompatibility antigen (MHC) class I and related molecules, the myeloid-expressed receptors appear to have a far more diverse range of functions and ligands, including those of exogenous origin. Some of C-type lectin-like molecules possess activating/inhibitory signalling motifs that trigger downstream signalling events, suggesting the role for these receptors as positive/negative regulators of granulocyte and monocyte functions. With the exception of a few myeloid NK-like lectins, the natural ligands for most of these receptors remain unidentified, making it difficult to define their functions in normal physiological, inflammatory or pathological conditions. Importantly, in some cases, these novel C-type lectin-like lectins, encoded by genes from the same gene cluster, can act as receptor/ligand pairs, additionally contributing to the regulation of myeloid cell functions or their interaction with other (like NK) cell types. However, the relevance and importance of such interactions still needs to be assessed. Although few of the myeloid-expressed C-type lectins have been characterized in detail, we review here each of these receptors and highlight their prospective roles in innate and adaptive immunity.

Animals↗

PubMed1982

C-reactive protein reactivity with complement and effects on phagocytosis.

In the studies described here we have attempted to evaluate the hypothesis that CRP may function in host defense using two systems in which CRP in the presence of C appears to have opsonic properties. In the first, CRP and C were found to stimulate ingestion of erythrocytes by human monocyte or mouse macrophages in vitro, and to alter clearance patterns in vivo. In the second, we have studied opsonization of S. pneumoniae by CRP and C. Experiments with human neutrophils indicate that although CRP and C can enhance opsonization of S. pneumoniae, this effect is more pronounced in the absence of antibody. In vivo CRP was found to protect mice against intravenous infection with S. pneumoniae.

Animals↗

PubMed2004

Interleukin-17: the missing link between T-cell accumulation and effector cell actions in rheumatoid arthritis?

The prominence of T cells and monocyte/macrophages in rheumatoid synovium suggests T cells may localize and amplify the effector functions of monocyte/macrophages in rheumatoid disease. However, while T cells are abundant in rheumatoid joints, classic T-cell derived cytokines are scarce, especially when compared to the levels of monokines IL-1 beta and TNF-alpha. For this reason, it has been speculated that monocyte/macrophages may act independently of T cells in rheumatoid disease and that the role of T cells may be more or less irrelevant to core disease mechanisms. The question of T-cell influence requires re-evaluation in light of the characterization of IL-17, a T-cell derived cytokine that is abundant in rheumatoid synovium and synovial fluid. IL-17 has a number of pro-inflammatory effects, both directly and through amplification of the effects of IL-1 beta and TNF-alpha. IL-17 is able to induce expression of pro-inflammatory cytokines and stimulate release of eicosanoids by monocytes and synoviocytes. Furthermore, IL-17 has been implicated in the pathogenesis of inflammatory bone and joint damage through induction of matrix metalloproteinases and osteoclasts, as well as inhibition of proteoglycan synthesis. In animal models of arthritis, intra-articular injection of IL-17 results in joint inflammation and damage. The recognition of IL-17 as a pro-inflammatory T cell derived cytokine, and its abundance within rheumatoid joints, provides the strongest candidate mechanism to date through which T cells can capture and localize macrophage effector functions in rheumatoid arthritis. As such, IL-17 warrants consideration for its potential as a therapeutic target in rheumatoid arthritis.

Animals↗

PubMed2004

Assessment of immunological parameters following a qigong training program.

BACKGROUND: Qigong is a type of Chinese psychosomatic exercise that integrates meditation, slow physical movements, and breathing, and to which numerous physical as well as mental benefits have been classically ascribed. The aim of the present study was to analyze the effects of a qigong program on various immunological parameters. MATERIAL/METHODS: 29 naive subjects participated in the study, of whom 16 were allocated to the experimental group and the rest to the control group. The experimental subjects underwent a qigong training program, conducted by a qualified instructor, consisting of half an hour of daily practice for one month. The day before the experiment commenced and the day after it finished, blood samples were drawn from all subjects for the quantification of immunological parameters (leukocytes, immunoglobulins, and complement). As statistical analysis, analysis of covariance (ANCOVA) was carried out. RESULTS: Statistically significant differences were found between the control and experimental groups, with the experimental group showing lower numbers of total leukocytes and eosinophils, number and percentage of monocytes, as well as complement C3 concentration. In addition, a similar result with a trend towards significance was observed in the number of eosinophils. CONCLUSIONS: These findings demonstrate that after one month of practicing qigong, significant immunological changes occurred between the experimental and control groups, with a consistently lower and broadly significant profile of these measures within the qigong practitioner group.

Adolescent↗

PubMed1992

Haematological differences between chronic granulocytic leukaemia, atypical chronic myeloid leukaemia, and chronic myelomonocytic leukaemia.

Chronic myeloid leukaemia (CML) is a generic term that include five apparently distinct entities. The best known form, the classical Ph-positive subtype, accounts for about 90% of all cases of CML. The morphology of its presentation blood film is highly characteristic but is also seen in about half of the remaining 10% of cases, which are Ph-negative. This classical morphological subtype, whether Ph-positive or Ph-negative I describe as 'chronic granulocytic leukaemia' to refer to the exuberant granulocytic proliferation which is its hallmark. This term is often used indiscriminately and interchangeably with 'chronic myeloid leukaemia' and similar terms, just as 'chronic lymphocytic leukaemia' was, until recently, used to cover the chronic lymphoid leukaemias in general, but is now used in a specific sense. Chronic granulocytic leukaemia (CGL), whether Ph-positive or Ph-negative, is almost always BCR-rearranged and associated with the production of a unique 210-kd protein with enhanced tyrosine kinase activity. Most of the remaining cases of Ph-negative CML are examples of either chronic myelomonocytic leukaemia (CMML), a subtype almost as homogeneous as CGL, and characterized in its presentation blood film by the presence of monocytes and neutrophils but few immature granulocytes, or atypical CML (aCML), distinct from and less homogeneous than either CGL or CMML, in which some cases also share features with CGL while others share some with CMML. CMML and aCML do not show BCR rearrangement and are not associated with the production of p210kd. CGL, CMML, and aCML, though characterized on morphological features differ in their clinical features and behaviour, response to treatment and survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗

PubMed2005

The cytokine-dependent MUTZ-3 cell line as an in vitro model for the screening of contact sensitizers.

Langerhans cells (LC) are key mediators of contact allergenicity in the skin. However, no in vitro methods exist which are based on the activation process of LC to predict the sensitization potential of chemicals. In this study, we have evaluated the performances of MUTZ-3, a cytokine-dependent human monocytic cell line, in its response to sensitizers. First, we compared undifferentiated MUTZ-3 cells with several standard human cells such as THP-1, KG-1, HL-60, K-562, and U-937 in their response to the strong sensitizer DNCB and the irritant SDS by monitoring the expression levels of HLA-DR, CD54, and CD86 by flow cytometry. Only MUTZ-3 and THP-1 cells show a strong and specific response to sensitizer, while other cell lines showed very variable responses. Then, we tested MUTZ-3 cells against a wider panel of sensitizers and irritants on a broader spectrum of cell surface markers (HLA-DR, CD40, CD54, CD80, CD86, B7-H1, B7-H2, B7-DC). Of these markers, CD86 proved to be the most reliable since it detected all sensitizers, including benzocaine, a classical false negative in local lymph node assay (LLNA) but not irritants. We confirmed the MUTZ-3 response to DNCB by real-time PCR analysis. Taken together, our data suggest that undifferentiated MUTZ-3 cells may represent a valuable in vitro model for the screening of potential sensitizers.

Adult↗

PubMed1987

Flow cytochemical patterns of white blood cells in human haematopoietic malignancies. I. Acute leukaemias.

Peripheral blood samples from 118 patients with acute leukaemia (68 untreated; 50 treated) were measured with the Technicon H-6000 automated haematology analyser. This instrument provides, in addition to measurements of the classical haematology parameters (i.e. cell counts, haemoglobin concentration, etc.), a differential count on 10(4) WBC effected by means of flow cytochemistry (peroxidase content) and volume (light scatter) discrimination. Disregarding RBC and platelet counts and their volume distribution profiles, the most important diagnostic parameters for leukaemic disease were the WBC count, the WBC differential count, and the proportions of large unstained cells (LUC) and high peroxidase (HPX) cells obtained by the automated differential count as well as the mean value of the WBC peroxidase content distribution (MPA). Granulocytic leukaemias had lower MPA than normal and lymphocytic leukaemias had MPA values above normal. M1 leukaemias were also characterized by large proportions of LUC and low fractions of HPX, while M2 leukaemias showed low LUC with high HPX. M3 leukaemias had low LUC and very high HPX. M4 leukaemias had large LUC and 'monocytic' components and a modest fraction of HPX. M5 leukaemias had very large numbers of LUC, 'monocytes' and 'lymphocytes' and a normal HPX. For M1 leukaemia, the presence of less than 7% LUC following induction treatment was related to morphological changes of normal cells induced by chemotherapy while LUC above 10% usually indicated unsuccessful induction associated with the presence of residual blasts. If treatment was successful, M2 and M3 leukaemias characteristically decreased their HPX population. All M4 leukaemias studied by us failed to enter remission and continued to display high proportions of HPX and LUC. Similarly, most M5 leukaemias had a poor response to treatment and always showed a very high proportion of LUC. Untreated lymphocytic leukaemias demonstrated high LUC, normal HPX and a high proportion of 'lymphocytes'. Hairy cell leukaemias showed almost equal proportions of 'lymphocytes' and LUC. Successful chemotherapy of all lymphoid leukaemia entities was associated with rapid decreases in LUC, slower decrements of 'lymphocytes' and moderate and transient increments in HPX. Thus, flow cytochemistry can assist not only in the segregation of acute leukaemias along with FAB classification with nonmorphologic criteria, but also in the follow up of patients with these diseases.

Acute Disease↗

PubMed2003

[Dendritic cells (DC) induced from acute myeloid leukemia (AML) cells with cytokine cocktails].

OBJECTIVES: To explore the feasibility of DC being in vitro induced from AML cells with cytokine cocktails and their biological properties. METHODS: AML cells were cultured in either presence or absence of cytokine cocktails. DC were studied for morphology, and cytochemical and immunofluorescent staining. Functions of DC were examined by MLC, FITC-conjugated dextran uptake test, and LDH release assay. RT-PCR and FISH were used to analyze the specific fusion genes of culture-derived DC. RESULTS: Classical DC morphological changes occurred in all 15 cultured AML cells. DC-associated surface molecules such as CD(1a), CD(80), CD(86), CD(106), CD(83) and HLA-DR were upregulated (P < 0.05). The allostimulatory abilities of culture-derived DC were significantly higher than those of AML cells uncultured or cultured in the absence of cytokines (P < 0.05). Culture-derived DC only in the presence of GM-CSF + IL-4 have phagocytotic activities. CTL assay was performed in 5 of the 15 samples. At effector/target ratio of 20:1, auto-T lymphocytes primed with the culture-derived DC exhibited no more killing activity to auto-AML cells than those stimulated by IL-2 or uncultured AML cells. Culture-derived DC presenced the native AML-specific aberrant karyotype and related fusion gene. CONCLUSIONS: Cytokine cocktails could in vitro induce AML cells into DC with classical morphology, immunophenotype and function. DC maturity induced by different cytokine cocktails could be variable. Culture-derived DC were originated from the native AML cells. AML cells could make the auto-T lymphocyte anergy.

Adolescent↗

PubMed2004

FTY720: early clinical experience.

FTY720 is the first in a new class of immunomodulators--sphingosine 1-phosphate receptor (S1P-R) agonists. It is highly effective in prolonging allograft survival in preclinical models of transplantation. Furthermore, FTY720 acts synergistically with calcineurin inhibitors and proliferation inhibitors in these models, suggesting that use of FTY720 in combination with classical immunosuppressants may be a promising new option for transplant patients. Phase I studies conducted in stable renal transplant patients maintained on a cyclosporine (CsA)-based regimen have revealed a tolerable profile of FTY720 for transplant pharmacotherapy. The pharmacokinetics of FTY720 is characterized by linear dose-proportional exposure over a wide range of doses, only moderate interpatient variability, and a prolonged elimination half-life (t(1/2) 89 to 157 hours). These factors suggest that FTY720 can be administered according to a simple once-daily schedule, without the need for blood-level monitoring or dose titration. The pharmacodynamics of FTY720 in humans are characterized by a significant reduction in peripheral blood count by up to 85%. In contrast to the nonspecific myelosuppressive effects of other immunosuppressants, this effect of FTY720 is specific for lymphocytes, with no effect observed on monocytes or granulocytes. In combination with CsA, FTY720 was well tolerated following single or multiple dosing, without any evidence of additional toxicities, indicating that FTY720 may be useful in the future design of more effective and less toxic regimens for prevention of graft rejection.

Animals↗

PubMed1988

Disease features in horses with induced equine monocytic ehrlichiosis (Potomac horse fever).

Fifty-five horses were inoculated IV and/or SC with materials containing Ehrlichia risticii, ie, infected whole blood, buffy coat cells, or cell culture, to study clinical and hematologic features of equine monocytic ehrlichiosis (Potomac horse fever). Major clinical and hematologic features of induced E risticii infection were biphasic increase in rectal temperature with peak increases of 38.9 C and 39.3 C on postinoculation days (PID) 5 and 12, respectively; depression; anorexia; decreased WBC count (maximal decrease of 47% on PID 12); and diarrhea from PID 14 to PID 18. Increased WBC count was an inconsistent feature, with a maximal increase of 51.5% on PID 20. During times of decreased and increased WBC counts, lymphocyte/neutrophil ratios remained fairly constant. However, not all horses had all clinical and hematologic features, and these features were present in different degrees among horses. Increased rectal temperature, depression, anorexia, and decreased WBC count were more consistent features, whereas diarrhea developed in 73% of the horses. Of 55 horses, 39 (71%) had all clinical and hematologic features of the disease (classic disease), whereas 16 (29%) horses did not have greater than or equal to 1 of these features (nonclassic disease). The E risticii titer in the blood (ehrlichemia) was maximum during the peak increase in rectal temperature. In 55 horses, mortality was 9%. Significant differences (P greater than 0.5) in clinical and hematologic features were not detected between horses that survived and those that died of E risticii infection.

Animals↗

PubMed1980

Complement receptors on normal human lymphocytes containing parallel tubular arrays.

Membrane complement receptors have been identified on a subpopulation of normal lymphocytes containing cytoplasmic inclusions called parallel tubular arrays (PTA) using two different rosetting techniques. The first technique utilizes as indicator cells erythrocytes that were coated with complement by the classic pathway of complement activation (EAC rosettes). The second technique utilizes as indicator cells Salmonella typhi, which were coated with complement by the alternate pathway of complement activation (FBC rosettes). In the latter technique, lipopolysaccharide material in the bacterial cell wall directly activates complement without the use of a sensitizing antibody. This eliminates binding of marker particles by lymphocytes having Fc receptors. The presence of PTA lymphocytes at the center of EAC rosettes and FBC rosettes was demonstrated by electron microscopy, indicating that the PTA lymphocyte has a complement receptor. Examination of FBC rosettes revealed that the adherent complement-coated bacteria were usually partially surrounded by pseudopodal extensions of the PTA lymphocyte. In addition, some PTA lymphocytes phagocytized the complement-coated bacteria but not the complement-inactivated bacteria. These phagocytic cells were placed in the lymphocytic series instead of the monocytic series by virtue of complete lack of endogenous peroxidase activity.

Bone Marrow↗

PubMed1990

Oestrogen receptors in macrophages.

The presence of receptors for oestradiol-17 beta and 5 alpha-dihydrotestosterone (5 alpha-DHT) in the human monocytic leukaemia cell line J111 and rat peritoneal macrophages was investigated using whole-cell assays. For both cell types, high-affinity binding species for oestrogen were detected, whereas no indication of specific binding was observed for 5 alpha-DHT. Analysis of the data according to Scatchard showed curved lines, indicating the presence of two different oestrogen-binding species. The dissociation constant (Kd) values for the receptors of the rat peritoneal macrophages were calculated to be 1.4 x 10(-10) M and 3.3 x 10(-9) M, while for the J111 cells, the Kd values were 8.7 x 10(-11) M and 2.5 x 10(-9) M. Sucrose-gradient ultracentrifugation identified one oestrogen-binding species of 7.1S. The receptors had a relatively high affinity for diethylstilboestrol (DES) but did not bind to a monoclonal antibody specific for the classical oestrogen receptor, suggesting that oestrogen receptors in macrophages could be of a different type.

Animals↗

PubMed2006

A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis.

Infection of human monocyte-derived macrophages with Mycobacterium tuberculosis at low multiplicities of infection leads 48-72 h after the infection to cell death with the characteristics of apoptosis or necrosis. Predominant induction of one or the other cell death modality depends on differences in mitochondrial membrane perturbation induced by attenuated and virulent strains. Infection of macrophages with the attenuated H37Ra or the virulent H37Rv causes mitochondrial outer membrane permeabilization characterized by cytochrome c release from the mitochondrial intermembrane space and apoptosis. Mitochondrial outer membrane permeabilization is transient, peaks 6 h after infection, and requires Ca(2+) flux and B cell chronic lymphocytic leukemia/lymphoma 2-associated protein X translocation into mitochondria. In contrast, only the virulent H37Rv induces significant mitochondrial transmembrane potential (Deltapsi(m)) loss caused by mitochondrial permeability transition. Dissipation of Deltapsi(m) also peaks at 6 h after infection, is transient, is inhibited by the classical mitochondrial permeability transition inhibitor cyclosporine A, has a requirement for mitochondrial Ca(2+) loading, and is independent of B cell chronic lymphocytic leukemia/lymphoma translocation into the mitochondria. Transient dissipation of Deltapsi(m) 6 h after infection is essential for the induction of macrophage necrosis by Mtb, a mechanism that allows further dissemination of the pathogen and development of the disease.

Calcium↗