scholarly journals Microfilariae of the Filarial Nematode Litomosoides sigmodontis Exacerbate the Course of Lipopolysaccharide-Induced Sepsis in Mice

2008 ◽  
Vol 76 (4) ◽  
pp. 1668-1677 ◽  
Author(s):  
Marc P. Hübner ◽  
Bastian Pasche ◽  
Svetoslav Kalaydjiev ◽  
Peter T. Soboslay ◽  
Andreas Lengeling ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Peripheral Blood ◽  
Inflammatory Responses ◽  
Interleukin 12 ◽  
Female Adult ◽  
Necrosis Factor Alpha ◽  
Lps Challenge ◽  
Litomosoides Sigmodontis ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Helminths facilitate their own survival by actively modulating the immune systems of their hosts. We investigated the impacts that different life cycle stages of the rodent filaria Litomosoides sigmodontis have on the inflammatory responses of mice injected with sublethal doses of lipopolysaccharide (LPS). Mice infected with female adult worms from prepatent infections, worms which have not yet started to release microfilariae, developed lower levels of proinflammatory cytokines in the peripheral blood after LPS challenge than sham-treated controls, demonstrating that female adult worms can mitigate the innate immune response. The presence of microfilariae in mice, however, through either direct injection or implantation of microfilaria-releasing adult female worms, turned the LPS challenge fatal. This lethal outcome was characterized by increased plasma levels of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), and IL-6, greater numbers of macrophages and granulocytes in the peripheral blood, and decreased body temperatures in microfilaria-infected mice. Microfilaria-infected mice deficient in IFN-γ receptor and TNF receptor 1 had increased survival rates after LPS challenge compared to immune-competent mice, suggesting that microfilariae worsen LPS-induced sepsis through actions of IFN-γ and TNF-α. In summary, we have demonstrated that infection of mice with L. sigmodontis female adult worms from prepatent infections protects mice injected with LPS whereas microfilariae worsen LPS-induced sepsis through the induction of proinflammatory cytokines and upregulation of granulocytes, NK cells, and monocytes in the peripheral blood.

scholarly journals Clinical and Immunologic Features of an Atypical Intracranial Mycobacterium avium Complex (MAC) Infection Compared with Those of Pulmonary MAC Infections

2008 ◽  
Vol 15 (10) ◽  
pp. 1580-1589 ◽  
Author(s):  
Mouhannad Sadek ◽  
Feng Yun Yue ◽  
Erika Yue Lee ◽  
Gabor Gyenes ◽  
R. Brad Jones ◽  
...  
Keyword(s):  
T Cell ◽  
Mycobacterium Avium ◽  
The Body ◽  
Interleukin 12 ◽  
Elderly Persons ◽  
Necrosis Factor Alpha ◽  
Healthy Elderly ◽  
Tnf Α ◽  
Ifn Γ ◽  
The Individual

ABSTRACT Members of the Mycobacterium avium complex (MAC) may cause chronic pulmonary infections in otherwise healthy elderly persons but rarely invade parts of the body outside of the lungs in immunocompetent hosts. We present a case of an isolated intracranial MAC infection in an apparently immunocompetent individual and review previous reports. We studied the T-cell and monocyte responses in healthy volunteers, individuals with a pulmonary MAC infection, and one individual with an isolated intracranial MAC infection. Genomic DNA from the individual with the brain MAC infection was studied for gamma interferon (IFN-γ) receptor mutations. Individuals with localized pulmonary MAC infections showed increased activation of monocytes and enhanced monocyte and T-cell tumor necrosis factor alpha (TNF-α) production in response to lipopolysaccharide and MAC antigens but defects in T-cell IFN-γ secretion. The individual with an intracranial MAC infection showed a lack of monocyte activation and deficiencies in both monocyte and T-cell TNF-α production and monocyte interleukin-12 (IL-12) production but had preserved T-cell IFN-γ production. Mutations or deletions in the IFN-γ receptor were not detected in the individual with the intracranial MAC infection. Our data suggest that distinct immune defects characterize two different manifestations of MAC infection. A relative defect in IFN-γ production in response to MAC may predispose an individual to localized but partially controlled lung disease, whereas defects leading to reduced IL-12 and TNF-α production may allow the dissemination of MAC. Further studies delineating the potential role of TNF-α in limiting the spread of MAC outside the lung are warranted.

scholarly journals Respiratory Tract Infection with Mycoplasma pneumoniae in Interleukin-12 Knockout Mice Results in Improved Bacterial Clearance and Reduced Pulmonary Inflammation

2006 ◽  
Vol 75 (1) ◽  
pp. 236-242 ◽  
Author(s):  
C. M. Salvatore ◽  
M. Fonseca-Aten ◽  
K. Katz-Gaynor ◽  
A. M. Gomez ◽  
A. Mejias ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Mycoplasma Pneumoniae ◽  
Pulmonary Inflammation ◽  
Airway Hyperreactivity ◽  
Interleukin 12 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Mycoplasma pneumoniae is a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniae respiratory disease severity with interleukin-12 (IL-12) concentration in respiratory secretions. We evaluated the microbiologic, inflammatory, and pulmonary function indices of M. pneumoniae pneumonia in IL-12 (p35) knockout (KO) mice and wild-type (WT) mice to determine the role of IL-12 in M. pneumoniae respiratory disease. Eight-week-old wild-type BALB/c mice and 8-week-old IL-12 (p35) KO BALB/c mice were inoculated once intranasally with 107 CFU of M. pneumoniae. Mice were evaluated at days 2, 4, and 7 after inoculation. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic scores (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor) and plethysmography, before and after methacholine, to assess airway obstruction (AO) and airway hyperreactivity (AHR). IL-12 (p35) KO mice infected with M. pneumoniae were found to have significantly lower BAL M. pneumoniae concentrations compared with M. pneumoniae-infected WT mice. Lung HPS and the parenchymal pneumonia subscores (neutrophilic alveolar infiltrate), as well as AO, were significantly lower in infected KO mice. No difference was found for AHR. Infected KO mice had significantly lower BAL concentrations of IFN-γ than WT mice; a trend toward lower BAL concentrations was observed for IL-10 (P = 0.065) and TNF-α (P = 0.078). No differences were found for IL-1β, IL-2, IL-4, IL-5, or IL-6. The lack of IL-12 in experimental M. pneumoniae pneumonia was associated with less severe pulmonary disease and more rapid microbiologic and histologic resolution.

scholarly journals Toll-Like Receptor 9 Is Required for Full Host Resistance toMycobacteriumaviumInfection but Plays No Role in Induction of Th1 Responses

2011 ◽  
Vol 79 (4) ◽  
pp. 1638-1646 ◽  
Author(s):  
Natália B. Carvalho ◽  
Fernanda S. Oliveira ◽  
Fernanda V. Durães ◽  
Leonardo A. de Almeida ◽  
Manuela Flórido ◽  
...  
Keyword(s):  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Histocompatibility Complex ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Myd88 Signaling ◽  
Necrosis Factor

ABSTRACTTo investigate the role of Toll-like receptor 9 (TLR9) in innate immunity toMycobacteriumavium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control ofM.aviuminfection. However, TLR9 KO or TLR2 KO spleen cells displayed normalM.avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4+T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production byM.avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes inM.avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control ofM.aviuminfection is not related to the induction of Th1 responses.

scholarly journals Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells

2017 ◽  
Vol 9 (5) ◽  
pp. 511-525 ◽  
Author(s):  
Sophie M. Poznanski ◽  
Amanda J. Lee ◽  
Tina Nham ◽  
Evan Lusty ◽  
Margaret J. Larché ◽  
...  
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Interleukin 12 ◽  
Tnf Α ◽  
Ifn Γ

The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation.

scholarly journals In Vivo Regulation of Replicative Legionella pneumophila Lung Infection by Endogenous Interleukin-12

1998 ◽  
Vol 66 (1) ◽  
pp. 65-69 ◽  
Author(s):  
J. K. Brieland ◽  
D. G. Remick ◽  
M. L. LeGendre ◽  
N. C. Engleberg ◽  
J. C. Fantone
Keyword(s):  
Legionella Pneumophila ◽  
Lung Infection ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin 12 (IL-12) in modulating intrapulmonary growth of Legionella pneumophila was assessed by using a murine model of replicative L. pneumophila lung infection. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophilacells per mouse) resulted in induction of IL-12, which preceded clearance of the bacteria from the lung. Inhibition of endogenous IL-12 activity, via administration of IL-12 neutralizing antiserum, resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection (compared to untreated L. pneumophila-infected mice). Because IL-12 has previously been shown to modulate the expression of cytokines, including gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-10, which regulate L. pneumophila growth, immunomodulatory effects of endogenous IL-12 on intrapulmonary levels of these cytokines during replicative L. pneumophila lung infection were subsequently assessed. Results of these experiments demonstrated that TNF-α activity was significantly lower, while protein levels of IFN-γ and IL-10 in the lung were similar, in L. pneumophila-infected mice administered IL-12 antiserum, compared to similarly infected untreated mice. Together, these results demonstrate that IL-12 is critical for resolution of replicativeL. pneumophila lung infection and suggest that regulation of intrapulmonary growth of L. pneumophila by endogenous IL-12 is mediated, at least in part, by TNF-α.

Phenotype and antitumor activity of ascitic fluid monocytes in patients with ovarian carcinoma

2003 ◽  
Vol 13 (4) ◽  
pp. 435-443 ◽  
Author(s):  
B. Melichar ◽  
C. A. Savary ◽  
R. Patenia ◽  
S. Templin ◽  
K. Melicharova ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Antigen Expression ◽  
Cytostatic Activity ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Color Flow ◽  
Uptake Inhibition ◽  
Ifn Γ

Monocytes/macrophages (MO/MA) represent a major leukocyte population in the peritoneal cavity of patients with epithelial ovarian cancer (EOC). We examined the phenotypic characteristics and antitumor cell activity of ascitic MO in patients with EOC. MO/MA phenotype was compared with MO in peripheral blood by two- and three-color flow cytometry. Cytotoxic/cytostatic effects of different cytokines on cultured EOC cells were measured by initial labeling or uptake inhibition of [methyl-3H] thymidine. Malignant ascites had higher proportion of MO/MA with the CD14brightCD16+ phenotype than peripheral blood. Cell surface antigen expression of activation and differentiation in peripheral blood and ascites, including CD38, CD40, CD64, and CD86, was higher on CD14brightCD16− and CD14brightCD16+ than on CD14dimCD16− cells. HLA-DR expression was higher on ascitic MO/MA than peripheral blood MO. Significant cytotoxic/cytostatic activity was elicited by treating ascitic MO/MA with interferon-γ (IFN-γ) and interleukin-2 (IL-2), but not with interleukin-12, paclitaxel, granulocyte-monocyte colony-stimulating factor (GM-CSF), or tumor necrosis factor-alpha (TNF-α). Soluble CD40Lt did not enhance MO/MA cytotoxic activity, and inhibited IFN-γ or IL-2 induced cytoxicity. We conclude that MO/MA from ascites have elevated proportions of CD14brightCD16+ cells, showing phenotypic features of activation. IFN-γ induces the cytotoxic and cytostatic activity of MO/MA that is inhibited by CD40Lt.

scholarly journals Comparison of Pathogenesis and Host Immune Responses to Candida glabrata and Candida albicans in Systemically Infected Immunocompetent Mice

2001 ◽  
Vol 69 (8) ◽  
pp. 5046-5055 ◽  
Author(s):  
Joan Brieland ◽  
David Essig ◽  
Craig Jackson ◽  
Doyle Frank ◽  
David Loebenberg ◽  
...  
Keyword(s):  
Host Defense ◽  
Proinflammatory Cytokines ◽  
Candida Glabrata ◽  
Interleukin 12 ◽  
Systemic Candidiasis ◽  
Rapid Induction ◽  
Tnf Α ◽  
Ifn Γ ◽  
Immunocompetent Mice ◽  
Intravenous Inoculation

ABSTRACT Cytokine-mediated host defense against Candida glabratainfection was compared to that against C. albicans, using immunocompetent murine models of systemic candidiasis. The pathogenesis of infection was evaluated morphologically and by culture of target organs, while the kinetics of induction of cytokine mRNAs and corresponding proteins were determined in kidneys by real-time reverse transcription-PCR and cytokine-specific murine enzyme-linked immunosorbent assays, respectively. Systemic infection with C. glabrata resulted in a chronic, nonfatal infection with recovery of organisms from kidneys, while intravenous inoculation with C. albicans resulted in rapid mortality with logarithmic growth of organisms in kidneys and recovery of C. albicans from the spleen, liver, and lungs. Survival of C. glabrata-infected mice was associated with rapid induction of mRNAs and corresponding immunoreactive proteins for the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), and gamma interferon (IFN-γ) and the lack of induction of protein for the anti-inflammatory cytokine IL-10. In contrast, mortality in C. albicans-infected mice was associated with induction of mRNA and corresponding protein for IL-10 but delayed (i.e., TNF-α) or absent (i.e., IL-12 and IFN-γ) induction of immunoreactive proinflammatory cytokines. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to TNF-α, IL-12, or IFN-γ, and the effect on growth of C. glabrata in kidneys was assessed. Neutralization of endogenous TNF-α resulted in a significant increase in C. glabrata organisms compared to similarly infected mice administered an isotype-matched control MAb, while neutralization of endogenous IL-12 or IFN-γ had no significant effect on C. glabrata replication. These results demonstrate that in response to intravenous inoculation of C. glabrata, immunocompetent mice develop chronic nonfatal renal infections which are associated with rapid induction of the proinflammatory cytokines TNF-α, IL-12, and IFN-γ. Furthermore, TNF-α plays a key role in host defense against systemic candidiasis caused by either C. glabrata or C. albicans, as the absence of endogenous TNF-α activity was associated with enhanced tissue burden in both infection models.

scholarly journals Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to Pulmonary Cryptococcus neoformans Infection

2002 ◽  
Vol 70 (6) ◽  
pp. 2959-2964 ◽  
Author(s):  
Amy C. Herring ◽  
John Lee ◽  
Roderick A. McDonald ◽  
Galen B. Toews ◽  
Gary B. Huffnagle
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Pulmonary Eosinophilia ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT The development of T1-cell-mediated immunity is required to clear a pulmonary Cryptococcus neoformans infection. The objective of these studies was to determine the mechanism by which tumor necrosis factor alpha (TNF-α) augments the development of pulmonary T1 immunity to C. neoformans infection. TNF-α expression was detected in lavage sample cells at days 2, 3, and 7 following C. neoformans infection. The numbers of CFU in the lung were not different between control and anti-TNF-α-treated mice at any time point examined during the afferent phase of the response (days 0 to 7). However, neutralization of TNF-α prevented the initiation of pulmonary clearance during the efferent phase of the response (day 14). Administration of anti-TNF-α monoclonal antibody (day 0) diminished the lung levels of TNF-α, interleukin-12 (IL-12), and gamma interferon (IFN-γ) induced by C. neoformans at day 7 postinfection. Neutralization of TNF-α (day 0) also altered the IFN-γ/IL-4 ratio in the lung-associated lymph nodes at day 7 following C. neoformans infection. Anti-TNF-α-treated mice developed a pulmonary eosinophilia at day 14 postinfection. Consistent with the pulmonary eosinophilia, anti-TNF-α-treated mice exhibited elevated serum immunoglobulin E and inhibition of the anticryptococcal delayed-type hypersensitivity response, indicating a shift toward a T2 response. Neutralization of IL-12 also prevented lung leukocyte production of IFN-γ in response to the infection. These findings demonstrate that afferent-phase TNF-α production is essential for the induction of IL-12 and IFN-γ and neutralization of early TNF-α results in a T2 shift of the T1/T2 balance of antifungal immunity.

scholarly journals Similar Cytokine Responses and Degrees of Anemia in Patients with Plasmodium falciparum and Plasmodium vivax Infections in the Brazilian Amazon Region

2008 ◽  
Vol 15 (4) ◽  
pp. 650-658 ◽  
Author(s):  
Andréa Aparecida Morais Fernandes ◽  
Leonardo José de Moura Carvalho ◽  
Graziela Maria Zanini ◽  
Ana Maria Revorêdo da Silva Ventura ◽  
José Maria Souza ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Brazilian Amazon ◽  
Immunoglobulin M ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Cytokine Responses ◽  
Tnf Α ◽  
Brazilian Amazon Region ◽  
Ifn Γ

ABSTRACT The mechanisms of malarial anemia induction are poorly understood, but cytokines and autoantibodies are considered to play important roles. This work aimed at evaluating the degree of anemia and the plasmatic profile of the cytokines tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), interleukin-12 (IL-12), migration inhibitory factor (MIF), and IL-10 and the monocyte chemotactic protein-1 (MCP-1) chemokine, as well as evaluating the presence of antibodies directed to components of the normal erythrocyte membrane and to cardiolipin in individuals with malaria from the Brazilian Amazon. No difference was observed in the frequency of anemia between patients infected by Plasmodium vivax and those infected by Plasmodium falciparum, and there was no relationship between the levels of parasitemia and the manifestations of anemia in P. vivax and P. falciparum patients. Significant increases in the concentrations of TNF-α, IFN-γ, MIF, and MCP-1 were observed in patients with P. falciparum and P. vivax malaria, whereas the concentrations of IL-10 was increased only in patients with P. vivax infection. Higher concentrations of IL-12 and IL-10 were observed in the P. falciparum anemic patients, while for TNF-α this profile was observed in the nonanemic ones. P. vivax-infected and P. falciparum-infected patients with positive immunoglobulin M (IgM) or IgM and IgG responses, respectively, against blood-stage forms of the parasites had significantly lower hemoglobin levels than did those with negative responses. There was no correlation between the presence of anti-erythrocyte and anti-cardiolipin antibodies and the presence or intensity of the anemia. Our data suggest that in areas of low endemicity and unstable transmission of malaria, P. vivax and P. falciparum infections present similar characteristics in terms of the induction of anemia and cytokine responses.

scholarly journals Dynamic Changes in Pro- and Anti-Inflammatory Cytokine Profiles and Gamma Interferon Receptor Signaling Integrity Correlate with Tuberculosis Disease Activity and Response to Curative Treatment

2006 ◽  
Vol 75 (2) ◽  
pp. 820-829 ◽  
Author(s):  
Edhyana Sahiratmadja ◽  
Bachti Alisjahbana ◽  
Tjitske de Boer ◽  
Iskandar Adnan ◽  
Anugrah Maya ◽  
...  
Keyword(s):  
Disease Activity ◽  
Disease Severity ◽  
Mycobacterial Infection ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Dynamic Changes ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory

ABSTRACT Pro- and anti-inflammatory cytokines and their signaling pathways play key roles in protection from and pathogenesis of mycobacterial infection, and their balance and dynamic changes may control or predict clinical outcome. Peripheral blood cells' capacity to produce proinflammatory (tumor necrosis factor alpha [TNF-α], interleukin-12/23p40 [IL-12/23p40], and gamma interferon [IFN-γ]) and anti-inflammatory (IL-10) cytokines in response to Mycobacterium tuberculosis or unrelated stimuli (lipopolysaccharide, phytohemagglutinin) was studied in 93 pulmonary tuberculosis (TB) patients and 127 healthy controls from Indonesia. Their cells' ability to respond to IFN-γ was examined to investigate whether M. tuberculosis infection can also inhibit IFN-γ receptor (IFN-γR) signaling. Although there was interindividual variability in the observed responses, the overall results revealed that M. tuberculosis-induced TNF-α and IFN-γ levels showed opposite trends. Whereas TNF-α production was higher in active-TB patients than in controls, IFN-γ production was strongly depressed during active TB, correlated inversely with TB disease severity, and increased during therapy. By contrast, mitogen-induced IFN-γ production, although lower in patients than in controls, did not change during treatment, suggesting an M. tuberculosis-specific and reversible component in the depression of IFN-γ. Depressed IFN-γ production was not due to decreased IL-12/IL-23 production. Importantly, IFN-γ-inducible responses were also significantly depressed during active TB and normalized during treatment, revealing disease activity-related and reversible impairment in IFN-γR signaling in TB. Finally, IFN-γ/IL-10 ratios significantly correlated with TB cure. Taken together, these results show that M. tuberculosis-specific stimulation of IFN-γ (but not TNF-α) production and IFN-γR signaling are significantly depressed in active TB, correlate with TB disease severity and activity, and normalize during microbiological TB cure. The depression of both IFN-γ production and IFN-γR signaling may synergize in contributing to defective host control in active TB.

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