The role of IL-12, IL-23 and IFN-γ in immunity to viruses

Novelli, Francesco; Casanova, Jean‐Laurent

doi:10.1016/j.cytogfr.2004.03.009

Cited by 103 publications

(83 citation statements)

References 159 publications

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“…However, the role of IL-12 in neuronal infection is unclear. IL-12 is induced by many viral infections of the CNS (20,50,55) and is a proinflammatory cytokine that plays a role in the development and maturation of a robust Th1, antiviral, adaptive immune response. However, while IL-12, a known inducer of IFN-␥ (80), is required for resolution of murine cytomegalovirus infection (53), IL-12 is not critical during LCMV infections, even though IFN-␥ function is necessary (54).…”

Section: Discussionmentioning

confidence: 99%

T Cell-, Interleukin-12-, and Gamma Interferon-Driven Viral Clearance in Measles Virus-Infected Brain Tissue

Park

Widness

Levine

et al. 2011

J Virol

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Genetic studies with immunocompetent mice show the importance of both T cells and gamma interferon (IFN-␥A wide variety of RNA and DNA viruses, including measles virus (MV), West Nile virus (WNV), human immunodeficiency virus, human cytomegalovirus, herpes simplex virus type 1 (HSV-1) and HSV-2, rabies virus, poliovirus, and lymphocytic choriomeningitis virus, cross the blood-brain barrier, infect the central nervous system (CNS), and cause encephalitis in mammals (3,15,26,29,34,35,75,82,85). A suitable combination of host inflammatory factors and the blood-borne viral load enables most viruses to enter the CNS. However, in the vast majority of cases, neuronal infection does not lead to overt CNS disease (82). Viral encephalitis detection rates, even when symptoms are severe, are very low (46), due in part to the poor sensitivity of the tools used to detect infection (21). However, with the increase in the number of immunocompromised individuals, whether through increasing populations of AIDS patients or pharmacologically compromised tissue transplant recipients, there has been a concomitant increase in viral encephalitis (11,77). Some viral infections, rather than being cleared by the host's immune system, result instead in high morbidity or mortality, often accompanied by severe inflammation (18,68,81). The balance between whether the adaptive immune response to a specific viral infection is protective or harmful is delicate, as many of the mechanisms that mediate inflammation in the CNS in both settings are similar (6,12,31,65).MV infection manifests itself primarily as a childhood illness with a characteristic macropapular rash. Measles is associated with high morbidity and mortality in developing countries, mostly due to a transient immunosuppression that leaves infected individuals highly susceptible to secondary infections (61). In approximately 0.1% of the cases, MV also causes CNS complications; one of these, subacute sclerosing panencephalitis (SSPE), is a progressive fatal disease. MV-associated encephalitis is one of many viral brain infections that cause high morbidity and mortality (26,34,85). The delayed pathogenesis of SSPE, including the route of viral entry into the CNS, is poorly understood (49). Although it is widely accepted that MV infection in the brain leads to complications, this is not necessarily the case, as MV mRNA is detected in the brains of 20% of individuals with no CNS pathology (33,34). It is currently hypothesized that SSPE is a result of mutated, aberrant

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Section: Discussionmentioning

confidence: 99%

T Cell-, Interleukin-12-, and Gamma Interferon-Driven Viral Clearance in Measles Virus-Infected Brain Tissue

Park

Widness

Levine

et al. 2011

J Virol

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“…Certain cytokines normally secreted by bone marrow stroma such as IL-12 and IL-15 are known to be required for IFN-␥ response. 19,20 Their up-regulation due to the absence of TC-PTP on bone marrow stromal cells could explain the abnormal secretion of IFN-␥, which further affects B-cell development. Another possibility is that the lack of TC-PTP creates an imbalance between proinflammatory and anti-inflammatory cytokines favoring proinflammatory virallike response.…”

Section: Discussionmentioning

confidence: 99%

TC-PTP–deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ

Bourdeau

Dubé

Heinonen

et al. 2007

Blood

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The T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of the Jak/Stat cytokine signaling pathway. Our study shows that the absence of TC-PTP leads to an early bone marrow B-cell deficiency characterized by hindered transition from the pre-B cell to immature B-cell stage. This phenotype is intrinsic to the B cells but most importantly due to bone marrow stroma abnormalities. We found that bone marrow stromal cells from TC-PTP ؊ IntroductionThe T-cell protein tyrosine phosphatase (TC-PTP) is an intracellular enzyme encoded by Ptpn2. It is ubiquitously expressed, with highest levels in hematopoietic tissues (for a review, see Bourdeau et al 1 ). TC-PTP Ϫ/Ϫ mice appear physically normal until 10 to 14 days of age, at which time they progressively develop tissue mononuclear cell infiltrates. 2 Elevated levels of IFN-␥ can be measured at 19 days of age, 3 and the animals die between 21 and 35 days of age. TC-PTP Ϫ/Ϫ mice display defective hematopoiesis and immune function, characterized by anemia and splenomegaly secondary to sequestration of erythrocytes and accumulation of myeloid cells. 2 TC-PTP was also shown to interact with TRAF2 downstream of the TNF proinflammatory cytokine. This interaction inactivated Src and suppressed MAPK signaling. 4 TC-PTP has been identified as a critical regulator of colony-stimulating factor 1 (CSF-1) signaling and mononuclear phagocyte development. On CSF-1 stimulation, a deficiency in TC-PTP leads to enhanced tyrosine phosphorylation of the Grb2/Gab2/Shp2 complex by the CSF-1 receptor and increased activation of Erk. 5 These results identified TC-PTP as a key modulator of inflammatory signals as well as macrophage and lymphocyte functions.TC-PTP has been shown to control cytokine signaling events by its negative action on the Janus kinase (Jak) and signal transducer and activator of transcription (Stat) pathways (reviewed by Bourdeau et al 1 ). This cascade is crucial for hematopoietic development and cellular response to growth factors. 6 Using an in vitro approach, TC-PTP substrate-trapping mutant D/A was shown to interact with Jak1 and Jak3. 7 Stat1, Stat3, and Stat5a/5b were also identified as substrates for TC-PTP. [8][9][10] It is clear that TC-PTP is a key director of several cytokine-signaling pathways, and thus may be involved in the development of multiple hematopoietic lineages.Here, we report that bone marrow stromal cells from TC-PTP Ϫ/Ϫ mice secrete abnormally high levels of IFN-␥, resulting in constitutive phosphorylation of Stat1 in pre-B cells and altered B-cell development in the bone marrow. Our findings are novel and reflect the therapeutic potential of TC-PTP as a modulator of bone marrow stroma microenvironment that could be exploited in leukemia and other immune disorders. Materials and methods MiceGeneration of TC-PTP mutant mice was described previously. 2 Experiments were performed with mice on a mixed Balb/c-129SJ background and with mice backcrossed for 8 generation on Balb/c. All procedures were approved by the McGill University Rese...

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“…IL-12 was measured in a DuoSet ELISA kit detecting the common p40 subunit of both IL-12 and IL-23 (R&D systems, Abingdon, UK). Since IL-12 and IL-23 bind also to a common receptor chain and have similar proinflammatory activities ( [33,34] and reviewed in [35]) we did not examine them separately.…”

Section: Quantification Of Proinflammatory Cytokines In Balmentioning

confidence: 99%

Lung Cell Tropism and Inflammatory Cytokine-Profile of Porcine Respiratory Coronavirus Infection

Atanasova¹,

Gucht²,

Barbé³

et al. 2008

TOVSJ

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Knowledge about porcine respiratory coronavirus (PRCV) tropism was limited to morphological identification of target cells and controversial reports on replication in macrophages. This study aimed to clarify the lung cell tropism of a Belgian PRCV strain and to examine the lung profile of inflammatory cytokines for 15 days after intratracheal PRCV inoculation of gnotobiotic piglets. Until 5 days after inoculation, more than 50% of the PRCV-positive cells were type 2 pneumocytes, 30% bronchiolar epithelial cells, and 10% macrophages, as demonstrated by immunofluorescence stainings with specific cell markers. In vitro, PRCV productively infected primary porcine lung epithelial cells, but not porcine alveolar macrophages. Bronchoalveolar lavage fluids of PRCV-inoculated pigs contained high levels of interferons (IFN-, IFN-) and interleukin-6, moderate interleukin-12 and low tumour necrosis factor-levels. Our results indicate that PRCV infects primarily type 2 pneumocytes and induces lower lung cytokine levels, compared to swine influenza virus or lipopolysaccharide-complicated PRCV infections.

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The role of IL-12, IL-23 and IFN-γ in immunity to viruses

Cited by 103 publications

References 159 publications

T Cell-, Interleukin-12-, and Gamma Interferon-Driven Viral Clearance in Measles Virus-Infected Brain Tissue

T Cell-, Interleukin-12-, and Gamma Interferon-Driven Viral Clearance in Measles Virus-Infected Brain Tissue

TC-PTP–deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ

Lung Cell Tropism and Inflammatory Cytokine-Profile of Porcine Respiratory Coronavirus Infection

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