scholarly journals Flavonoid Mixture Inhibits Mycobacterium tuberculosis Survival and Infectivity

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 851 ◽  
Author(s):  
Ruoqiong Cao ◽  
Garrett Teskey ◽  
Hicret Islamoglu ◽  
Myra Gutierrez ◽  
Oscar Salaiz ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Healthy Subjects ◽  
Granuloma Formation ◽  
Pathogenic Potential ◽  
Flavonoid Intake ◽  
Favorable Influence ◽  
Ifn Γ ◽  
Healthy Participants

Background: Flavonoids have been shown to exert anti-pathogenic potential, but few studies have investigated their effects on Mycobacterium tuberculosis (Mtb) infectivity. We hypothesized that a flavonoid mixture would have a favorable influence on cell death and the resolution of Mtb infection in THP-1 macrophages and in granulomas derived from both healthy participants and those with type 2 diabetes mellitus (T2DM). METHODS: THP-1 macrophages, and in vitro granulomas from healthy participants (N = 8) and individuals with T2DM (N = 5) were infected with Mtb. A mixed flavonoid supplement (MFS) at a concentration of 0.69 mg per ml was added as treatment to Mtb infected THP-1 macrophages and granulomas for 8 to 15 days. RESULTS: MFS treatment significantly reduced the intracellular Mtb survival, increased cell density, aggregation, and granuloma formation, and increased glutathione (GSH) levels. IL-12 and IFN-γ levels tended to be higher and IL-10 lower when Mtb infected THP-1 macrophages and granulomas obtained from healthy subjects were treated with MFS compared to control. CONCLUSIONS: MFS treatment exerted a strong influence against Mtb infectivity in THP-1 macrophages and in granulomas including antimycobacterial effects, GSH enrichment, cytokine regulation, and augmented granuloma formation. Our data support the strategy of increased flavonoid intake for managing tuberculosis.

scholarly journals The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering the Immune Responses against Mycobacterium bovis BCG Strain in Individuals with Type 2 Diabetes

2021 ◽  
Vol 12 (1) ◽  
pp. 16-26
Author(s):  
Kimberly To ◽  
Ruoqiong Cao ◽  
Aram Yegiazaryan ◽  
James Owens ◽  
Kayvan Sasaninia ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Immune Cells ◽  
Mycobacterial Infection ◽  
Drug Resistant ◽  
Tnf Α ◽  
Resistant Strains ◽  
Ifn Γ ◽  
Drug Resistant Strains

Abstract Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains a devastating infectious disease in the world. There has been a daunting increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. T2DM patients are three times more vulnerable to M. tb infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research, M. tb still has unexplored characteristics in successfully evading host defenses. The lengthy duration of treatment, the emergence of multi-drug-resistant strains and extensive-drug-resistant strains of M. tb have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within in vitro granulomas generated from immune cells derived from peripheral blood of healthy subjects. However, the effectiveness of everolimus treatment against mycobacterial infection in individuals with T2DM is unknown. Furthermore, the effectiveness of the combination of in vivo glutathione (GSH) supplementation in individuals with T2DM along with in vitro treatment of isolated immune cells with everolimus against mycobacterial infection has never been tested. Therefore, we postulated that liposomal glutathione (L-GSH) and everolimus would offer great hope for developing adjunctive therapy for mycobacterial infection. L-GSH or placebo was administered to T2DM individuals orally for three months. Study subjects’ blood was drawn pre- and post-L-GSH/or placebo supplementation, where Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood to conduct in vitro studies with everolimus. We found that in vitro treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular M. bovis BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with in vitro everolimus treatment produced a greater effect in inhibiting the growth of intracellular Mycobacterium bovis BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with in vitro everolimus treatment in modulating the levels of cytokines such as IFN-γ, TNF-α, and IL-2 and IL-6, in favor of improving control of the mycobacterial infection. In summary, in vitro everolimus-treatment alone and in combination with oral L-GSH supplementation for three months in individuals with T2DM, was able to increase the levels of T-helper type 1 (Th1) cytokines IFN-γ, TNF-α, and IL-2 as well as enhance the abilities of granulomas from individuals with T2DM to improve control of a mycobacterial infection.

scholarly journals PERCENTAGE OF CD3+ T LYMPHOCYTES EXPRESSING IFN-γ AFTER CFP-10 STIMULATION (Persentase Limfosit T-CD3+ yang Mengekspresikan Interferon Gamma Setelah Stimulasi Antigen CFP-10)

2018 ◽  
Vol 23 (1) ◽  
pp. 31
Author(s):  
Yulia Nadar Indrasari ◽  
Betty Agustina Tambunan ◽  
Jusak Nugraha ◽  
Fransiska Sri Oetami
Keyword(s):  
Flow Cytometry ◽  
Mycobacterium Tuberculosis ◽  
T Lymphocytes ◽  
Interferon Gamma ◽  
Tuberculosis Antigen ◽  
Mycobacterium Tuberculosis Antigen ◽  
Ifn Γ

Tuberkulosis (TB) merupakan penyakit infeksi menular, disebabkan oleh Mycobacterium tuberculosis. Respons imun adaptif yangdiperantarai oleh limfosit T berperan sangat penting dalam menyingkirkan bakteri intraseluler. Hasilan sitokin IFN-γ merupakanmekanisme efektor utama dari limfosit T. Pengembangan vaksin yang efektif dalam melawan infeksi TB mempertimbangkan faktor yangmengatur hasilan IFN-γ. CFP-10 merupakan antigen yang disekresikan oleh Mycobacterium tuberculosis. Antigen ini dikenal sebagaikomponen vaksin potensial untuk TB. Tujuan penelitian ini adalah membandingkan respons imun seluler yaitu persentase limfosit T-CD3+yang mengekspresikan IFN-γ setelah dirangsang antigen CFP-10 di pasien TB paru kasus baru, TB laten dan orang sehat. Penelitianini menggunakan desain eksperimen murni di laboratorium secara in vitro pada kultur PBMC pasien TB paru kasus baru, TB latendan orang sehat. Subjek penelitian adalah 8 pasien TB paru kasus baru, 7 TB laten dan 7 orang sehat di RS Khusus Paru Surabaya.Pemeriksaan persentase limfosit T-CD3+ yang mengekspresikan IFN-γ dengan metode Flow cytometry (BD FACSCalibur). Hasil dianalisisdengan Kruskal-Wallis atau ANOVA satu arah. Rerata persentase limfosit T-CD3+ yang mengekspresikan IFN-γ di TB paru kasus barusetelah stimulasi antigen CFP-10 (4,36%) lebih tinggi daripada sebelum stimulasi (3,50%) (nilai P=0,015). Rerata persentase limfositT-CD3+ yang mengekspresikan IFN-γ di TB laten setelah stimulasi antigen CFP-10 (3,96%) lebih tinggi dibandingkan sebelum stimulasi(2,50%) tetapi tidak bermakna (nilai P=0,367). Rerata persentase limfosit T- CD3+ yang mengekspresikan IFN-γ di orang sehat setelahstimulasi (1,66%) lebih rendah daripada sebelum stimulasi (2,89%) tetapi tidak bermakna (nilai P=0,199). Perubahan persentaselimfosit T-CD3+ yang mengekspresikan IFN-γ setelah stimulasi antigen CFP-10 antarkelompok tidak berbeda bermakna (nilai P=0,143).Berdasarkan hasil telitian ini dapat disimpulkan bahwa terdapat peningkatan persentase limfosit T-CD3+ yang mengekspresikan IFN-γdi TB paru kasus baru setelah stimulasi antigen CFP-10. Hal ini menunjukkan limfosit T-CD3+ yang mengekspresikan IFN-γ berperandalam perlindungan terhadap infeksi TB paru.

scholarly journals Urban airborne particle exposure impairs human lung and blood Mycobacterium tuberculosis immunity

Thorax ◽  
2019 ◽  
Vol 74 (7) ◽  
pp. 675-683 ◽  
Author(s):  
Martha Torres ◽  
Claudia Carranza ◽  
Srijata Sarkar ◽  
Yolanda Gonzalez ◽  
Alvaro Osornio Vargas ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mexico City ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Human Lung ◽  
Constitutive Expression ◽  
In Vitro Exposure ◽  
Ifn Γ

RationaleAssociations between urban (outdoor) airborne particulate matter (PM) exposure and TB and potential biological mechanisms are poorly explored.ObjectivesTo examine whether in vivo exposure to urban outdoor PM in Mexico City and in vitro exposure to urban outdoor PM2.5 (< 2.5 µm median aerodynamic diameter) alters human host immune cell responses to Mycobacterium tuberculosis.MethodsCellular toxicity (flow cytometry, proliferation assay (MTS assay)), M. tuberculosis and PM2.5 phagocytosis (microscopy), cytokine-producing cells (Enzyme-linked immune absorbent spot (ELISPOT)), and signalling pathway markers (western blot) were examined in bronchoalveolar cells (BAC) and peripheral blood mononuclear cells (PBMC) from healthy, non-smoking, residents of Mexico City (n=35; 13 female, 22 male). In vivo-acquired PM burden in alveolar macrophages (AM) was measured by digital image analysis.Measurements and main resultsIn vitro exposure of AM to PM2.5 did not affect M. tuberculosis phagocytosis. High in vivo-acquired AM PM burden reduced constitutive, M. tuberculosis and PM-induced interleukin-1β production in freshly isolated BAC but not in autologous PBMC while it reduced constitutive production of tumour necrosis factor-alpha in both BAC and PBMC. Further, PM burden was positively correlated with constitutive, PM, M. tuberculosis and purified protein derivative (PPD)-induced interferon gamma (IFN-γ) in BAC, and negatively correlated with PPD-induced IFN-γ in PBMC.ConclusionsInhalation exposure to urban air pollution PM impairs important components of the protective human lung and systemic immune response against M. tuberculosis. PM load in AM is correlated with altered M. tuberculosis-induced cytokine production in the lung and systemic compartments. Chronic PM exposure with high constitutive expression of proinflammatory cytokines results in relative cellular unresponsiveness.

scholarly journals The Intracellular Growth of M. tuberculosis Is More Associated with High Glucose Levels Than with Impaired Responses of Monocytes from T2D Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Martha Torres ◽  
María Teresa Herrera ◽  
Guadalupe Fabián-San-Miguel ◽  
Yolanda Gonzalez
Keyword(s):  
High Glucose ◽  
Healthy Subjects ◽  
Intrinsic Factor ◽  
Growth Control ◽  
Intracellular Growth ◽  
Glucose Levels ◽  
Basal Expression ◽  
Ligand Stimulation

Diabetes mellitus, a metabolic disease characterized by hyperglycemia and poor glucose control, is a risk factor for Mycobacterium tuberculosis (M. tuberculosis) infection and the development of active tuberculosis. To evaluate whether M. tuberculosis infection susceptibility is associated with an intrinsic factor in monocytes from type 2 diabetes (T2D) patients or it is associated with hyperglycemia per se, we analyzed TLR-2 and TLR-4 expression by flow cytometry and the cytokines IL-1β, IL-6, IL-8, IL-10, and TNF-α by cytometric bead array assays, either stimulated with TLR-2 and TLR-4 ligands or infected with M. tuberculosis in the whole blood from T2D patients (n=43) and healthy subjects (n=26) or in CD14+ monocytes from healthy subjects cultured in high glucose (HG) (30 mM). The intracellular growth of M. tuberculosis was evaluated by CFU counts at 0, 1, and 3 days in both monocytes from T2D patients and monocytes from healthy subjects cultured in HG. We did not find significant differences in TLR expression, cytokine production, or growth of M. tuberculosis in monocytes from T2D patients compared with those in monocytes from healthy subjects. Despite these results, in vitro assays of monocytes cultured with 30 mM glucose led to significantly increased TLR-2 and TLR-4 basal expression compared to those of monocytes cultured with 11 mM glucose (P<0.05). Conversely, the production of IL-6 by TLR-2 ligand stimulation, of IL-1β, IL-6, and IL-8 by TLR-4 ligand stimulation, and of IL-8 by M. tuberculosis infection significantly decreased in monocytes cultured in HG (P<0.05). Additionally, the intracellular survival of M. tuberculosis increased in monocytes in HG after day 3 of culture (P<0.05). In conclusion, HG decreased IL-8 production and the intracellular growth control of M. tuberculosis by monocytes, supporting the hypothesis that hyperglycemia plays an important role in the impaired immune responses to M. tuberculosis in patients with T2D.

Cultured Human B Cell APCs Expanded Using Il-4 and CD40 Ligand Preferentially Promote a Type 2 T Cell Response to Alloimmune Stimulation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2668-2668
Author(s):  
Abdul Tawab ◽  
Yoshiyuki Takahashi ◽  
Childs Richard ◽  
Kurlander J. Roger
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Cd40 Ligand ◽  
T Cell Response ◽  
Ifn Γ

Abstract In vitro stimulation of human peripheral blood B cells with recombinant IL-4 and CD40 ligand (CD40L) markedly increases their expression of MHC and costimulatory molecules, thus enhancing antigenic peptide presentation to T cells. Because these cells proliferate extensively in vitro (unlike monocytes or dendritic cells), they represent a promising and convenient reagent for the generation and maintenance of antigen-specific T cells for use in a variety of experimental or therapeutic settings. However, the impact of this type of B cell APC on cytokine production by responder T cells has hitherto not been examined. To address this issue, we stimulated normal human T cells with either allogeneic B cells (generated in vitro) or with MNCs obtained from the same donor. After 7 days, T cells were washed and re-challenged with the same APCs. The resulting alloreactive cytokine response was measured using quantitative ELISPOT methods and expressed as the frequencies of IFN-γ, IL-4, and IL-5 producing cells per thousand responder cells added. B cell- and MNC-primed cell lines both produced vigorous lymphokine responses, but B cell-stimulated T cells consistently produced more IL-5 spots (mean of 265 vs. 98/1000 responders, p<0.002) and fewer IFN-γ spots (163 vs 386/1000 cells, p<0.005) than MNC-stimulated cells. Further, the ratio of IFN-γ to IL-5 spots was almost ten-fold lower in B cell-stimulated cultures compared to MNC-induced cultures (0.67 vs. 5.2, p<0.001). ELISPOT studies assessing the ratio of IFN-γ to IL-4 spots and ELISA assays comparing IFN-γ and IL-5 levels from culture supernatants demonstrated the same pattern of marked type 2 skewing by B cells. This pattern was unaffected by the presence of anti-IL-4 antibody suggesting type 2 skewing was not mediated by IL-4. Cytokine skewing produced by B cells or MNC could be partially reversed by swapping MNC and B cells during re-stimulation on day 7, but this plasticity was markedly reduced after 3 (weekly) cycles of B cell or MNC re-stimulation in vitro. Type 2 skewing by B cells was enhanced when monocytes were removed from responder T cell populations by either depleting CD14+ positive cells or by positive selection of T cells prior to stimulation. In contrast, type 2 polarization could be prevented using recombinant IL-12. Not all cells of B-cell origin share the same propensity to type 2 skewing observed with IL-4/CD40L-stimulated B cells; under identical conditions, EBV-transformed B cells stimulated alloimmune T cells to produce a strong type 1 cytokine response comparable to that produced by MNCs. In summary, IL-4/CD40L-stimulated B cells strongly promote a type 2 T cell response during primary alloimmune challenge; this skewing can become fixed after repeated B cell stimulation. Investigators using these cells as APC should be aware of this potential phenomenon, particularly during primary T cell responses. It is also important to consider the factors described above that may exacerbate or ameliorate this effect.

scholarly journals Dispensability of Surfactant Proteins A and D in Immune Control ofMycobacterium tuberculosisInfection following Aerosol Challenge of Mice

2011 ◽  
Vol 79 (3) ◽  
pp. 1077-1085 ◽  
Author(s):  
Maria P. Lemos ◽  
John McKinney ◽  
Kyu Y. Rhee
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Low Dose ◽  
Fungal Infections ◽  
T Cell Response ◽  
Surfactant Proteins ◽  
Cell Populations ◽  
Immune Control ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACTSurfactant proteins A and D (SP-A and -D) play a role in many acute bacterial, viral, and fungal infections and in acute allergic responses.In vitro, human SPs bindMycobacterium tuberculosisand alter human and rat macrophage-mediated functions. Here we report the roles of SP-A and SP-D inM. tuberculosisinfection following aerosol challenge of SP-A-, SP-D-, and SP-A/-D-deficient mice. These studies surprisingly identified no gross defects in uptake or immune control ofM. tuberculosisin SP-A-, SP-D-, and SP-A/-D-deficient mice. While both SP-A- and SP-D-deficient mice exhibited evidence of immunopathologic defects, the CD11bhighCD11chighdendritic cell populations and the gamma interferon (IFN-γ)-dependent CD4+T cell response toM. tuberculosiswere unaltered in all genotypes tested. Together, these data indicate that SP-A and SP-D are dispensable for immune control ofM. tuberculosisin a low-dose, aerosol challenge, murine model of tuberculosis (TB).

scholarly journals Tissue factor and Toll-like receptor (TLR)4 in hyperglycaemia-hyperinsulinaemia

2015 ◽  
Vol 113 (04) ◽  
pp. 750-758 ◽  
Author(s):  
Anamika Singh ◽  
Guenther Boden ◽  
A. Koneti Rao
Keyword(s):  
Tissue Factor ◽  
Healthy Subjects ◽  
Toll Like Receptor ◽  
Elevated Plasma ◽  
Type 2 Dm ◽  
Type 1 Dm

SummaryDiabetes mellitus (DM) patients have an increased incidence of cardiovascular events. Blood tissue factor-procoagulant activity (TF-PCA), the initiating mechanism for blood coagulation, is elevated in DM. We have shown that hyperglycaemia (HG), hyperinsulinaemia (HI) and combined HG+HI (induced using 24-hour infusion clamps) increases TF-PCA in healthy and type 2 DM (T2DM) subjects, but not in type 1 DM (T1DM) subjects. The mechanisms for this are unknown. DM patients have elevated plasma lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. We postulated that TLR4 plays a role in modulating TF levels. We studied the effect of HG+HI on TLR4 and TF-PCA in vivo during 24-hour HG+HI infusion clamps in healthy subjects, and T1DM and T2DM subjects, and in vitro in blood. In vivo, in healthy subjects, 24-hour HG + HI infusion increased TLR4 six-fold, which correlated with TF-PCA (r=0.91, p<0.0001). T2DM patients showed smaller increases in both. In T1DM subjects, TLR4 declined (50%, p<0.05) and correlated with TF-PCA (r=0.55; p<0.05). In vitro, HG (200 mg/dl added glucose) and HI (1-100 nM added insulin) increased TF-PCA in healthy subjects (˜2-fold, 2-4 hours). Insulin inhibited by ~30% LPSinduced increase in TF-PCA and high glucose reversed it. TLR4 levels paralleled TF-PCA (r=0.71, p<0.0001); HG and HI increased TLR4 and insulin inhibited LPS-induced TLR4 increase. This is first evidence that even in healthy subjects, HG of short duration increases TLR4 and TFPCA, key players in inflammation and thrombosis. TLR4-TF interplay is strikingly different in non-diabetic, T1DM and T2DM subjects.

scholarly journals Incubation of Whole Blood at 39°C Augments Gamma Interferon (IFN-γ)-Induced Protein 10 and IFN-γ Responses to Mycobacterium tuberculosis Antigens

2011 ◽  
Vol 18 (7) ◽  
pp. 1150-1156 ◽  
Author(s):  
Martine G. Aabye ◽  
Pernille Ravn ◽  
Isik S. Johansen ◽  
Jesper Eugen-Olsen ◽  
Morten Ruhwald
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Whole Blood ◽  
Incubation Temperature ◽  
Gamma Interferon ◽  
Content Type ◽  
Interleukin 7 ◽  
Ifn Γ

ABSTRACTA rarely challenged dogma in cell-mediated immune (CMI) assays is the incubation temperature, 37°C. Fever augments proinflammatory immune responsesin vivo, and the aim of this study was to explore whether incubation at fever-range temperature could increase antigen-specific biomarker responses. We compared CMI responses following incubation of whole blood at 37°C and 39°C. Whole blood was obtained from (i) 34 healthy subjects whose blood was incubated with TB10.4 antigen, present in theMycobacterium bovisbacillus Calmette-Guérin vaccine and many environmental mycobacteria; (ii) 8 TB patients and 8 controls incubated withMycobacterium tuberculosis-specific antigens in the QuantiFERON-TB Gold test (QFT-IT); and (iii) from both groups incubated with a T cell mitogen. T cell responses (gamma interferon [IFN-γ]) and responses from antigen-presenting cells (IFN-γ-induced protein 10 [IP-10]) were determined. We further evaluated the effect of adding interleukin-7 (IL-7) and blocking IL-10 during incubation. In TB patients, IFN-γ and IP-10 levels were increased 4.1- and 3.4-fold, respectively, at 39°C incubation (P< 0.001). Similar results were seen after mitogen stimulation. In subjects responding to TB10.4, the effects were less pronounced and significant only for IP-10. Incubation at 39°C increased IP-10 and IFN-γ responsiveness to both antigens and mitogen in persons with baseline or initial low responses. Adding IL-7 and blocking IL-10 augmented the effects in synergy with fever-range temperature. Incubation at fever-range temperature vividly increases CMI responsiveness to antigen stimulationin vitroin tuberculosis patients and may increase the sensitivity of CMI assays.

An in vitro model of the leukocyte interactions associated with granuloma formation in Mycobacterium tuberculosis infection

2007 ◽  
Vol 85 (2) ◽  
pp. 160-168 ◽  
Author(s):  
Kristin A Birkness ◽  
Jeannette Guarner ◽  
Suraj B Sable ◽  
Ralph A Tripp ◽  
Kathryn L Kellar ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
In Vitro Model ◽  
Granuloma Formation ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Vitro Model

scholarly journals MyD88 Primes Macrophages for Full-Scale Activation by Interferon-γ yet Mediates Few Responses to Mycobacterium tuberculosis

2003 ◽  
Vol 198 (7) ◽  
pp. 987-997 ◽  
Author(s):  
Shuangping Shi ◽  
Carl Nathan ◽  
Dirk Schnappinger ◽  
Jörg Drenkow ◽  
Michele Fuortes ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Large Scale ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Full Scale ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ifn Γ ◽  
Microbial Products ◽  
Oxide Synthase

Macrophages are activated from a resting state by a combination of cytokines and microbial products. Microbes are often sensed through Toll-like receptors signaling through MyD88. We used large-scale microarrays in multiple replicate experiments followed by stringent statistical analysis to compare gene expression in wild-type (WT) and MyD88−/− macrophages. We confirmed key results by quantitative reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Surprisingly, many genes, such as inducible nitric oxide synthase, IRG-1, IP-10, MIG, RANTES, and interleukin 6 were induced by interferon (IFN)-γ from 5- to 100-fold less extensively in MyD88−/− macrophages than in WT macrophages. Thus, widespread, full-scale activation of macrophages by IFN-γ requires MyD88. Analysis of the mechanism revealed that MyD88 mediates a process of self-priming by which resting macrophages produce a low level of tumor necrosis factor. This and other factors lead to basal activation of nuclear factor κB, which synergizes with IFN-γ for gene induction. In contrast, infection by live, virulent Mycobacterium tuberculosis (Mtb) activated macrophages largely through MyD88-independent pathways, and macrophages did not need MyD88 to kill Mtb in vitro. Thus, MyD88 plays a dynamic role in resting macrophages that supports IFN-γ–dependent activation, whereas macrophages can respond to a complex microbial stimulus, the tubercle bacillus, chiefly by other routes.

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