Staphylococcal Enterotoxin B Upregulates Expression of ICAM-1 Molecules on IFN-γ-Treated Keratinocytes and Keratinocyte Cell Lines

ABSTRACTStaphylococcal enterotoxin B (SEB) causes food poisoning in humans. It is considered a biological weapon, and inhalation can trigger lung injury and sometimes respiratory failure. Being a superantigen, SEB initiates an exaggerated inflammatory response. While the role of microRNAs (miRNAs) in immune cell activation is getting increasing recognition, their role in the regulation of inflammatory disease induced by SEB has not been studied. In this investigation, we demonstrate that exposure to SEB by inhalation results in acute inflammatory lung injury accompanied by an altered miRNA expression profile in lung-infiltrating cells. Among the miRNAs that were significantly elevated, miR-155 was the most overexpressed. Interestingly, miR-155−/−mice were protected from SEB-mediated inflammation and lung injury. Further studies revealed a functional link between SEB-induced miR-155 and proinflammatory cytokine gamma interferon (IFN-γ). Through the use of bioinformatics tools, suppressor of cytokine signaling 1 (SOCS1), a negative regulator of IFN-γ, was identified as a potential target of miR-155. While miR-155−/−mice displayed increased expression ofSocs1, the overexpression of miR-155 led to its suppression, thereby enhancing IFN-γ levels. Additionally, the inhibition of miR-155 resulted in restoredSocs1expression. Together, our data demonstrate an important role for miR-155 in promoting SEB-mediated inflammation in the lungs throughSocs1suppression and suggest that miR-155 may be an important target in preventing SEB-mediated inflammation and tissue injury.

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Staphylococcal Enterotoxin B In Vivo Modulates both Gamma Interferon Receptor Expression and Ligand-Induced Activation of Signal Transducer and Activator of Transcription 1 in T Cells

Infection and Immunity ◽

10.1128/iai.01220-06 ◽

2006 ◽

Vol 75 (1) ◽

pp. 306-313 ◽

Cited By ~ 11

Author(s):

R. Plaza ◽

J. L. Rodriguez-Sanchez ◽

C. Juarez

Keyword(s):

T Cells ◽

Gamma Interferon ◽

Staphylococcal Enterotoxin ◽

Receptor Expression ◽

Protective Mechanism ◽

Staphylococcal Enterotoxin B ◽

Selective Blockade ◽

Stat1 Signaling ◽

Ifn Γ ◽

Enterotoxin B

ABSTRACT Superantigens (SAg) are bacterial exotoxins that provoke extreme responses in the immune system; for example, the acute hyperactivation of SAg-reactive T cells that leads to toxic shock syndrome is followed within days by strong immunosuppression. The gamma interferon (IFN-γ) response is deeply affected in both extremes. The implication of IFN-γ in the pathophysiology of lethal shock induced in mice after a secondary challenge with the SAg staphylococcal enterotoxin B (SEB) prompted us to study the regulation of IFN-γ secretion and the intracellular response. We demonstrate in this study that a rechallenge with SEB becomes lethal only when given inside a critical time window after SEB priming and is associated with an increase of IFN-γ serum release 72 h after priming. However, at this time, a selective blockade of IFN-γ/STAT1 signaling develops in spleen cells, correlating with a lack of expression of the IFN-γ receptor beta subunit and STAT1 in the T-cell population. Selective blockade of the STAT1 signaling pathway—while simultaneously maintaining STAT3 signaling and expression—may be a protective mechanism that shortens IFN-γ production during the Th1 effector response. This blockade may also have consequences on switching towards a suppressor phenotype with chronic exposure to the superantigen.

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Differential Regulation of Cytokine Production by CD1d-Restricted NKT Cells in Response to Superantigen Staphylococcal Enterotoxin B Exposure

Infection and Immunity ◽

10.1128/iai.74.1.282-288.2006 ◽

2006 ◽

Vol 74 (1) ◽

pp. 282-288 ◽

Cited By ~ 11

Author(s):

Melanie J. Ragin ◽

Nisebita Sahu ◽

Avery August

Keyword(s):

T Cells ◽

T Cell ◽

Interleukin 2 ◽

Nkt Cells ◽

Staphylococcal Enterotoxin ◽

Cytokine Secretion ◽

Staphylococcal Enterotoxin B ◽

Tnf Α ◽

Ifn Γ ◽

Enterotoxin B

ABSTRACT NKT cells are a heterogeneous population characterized by the ability to rapidly produce cytokines, such as interleukin 2 (IL-2), IL-4, and gamma interferon (IFN-γ) in response to infections by viruses, bacteria, and parasites. The bacterial superantigen staphylococcal enterotoxin B (SEB) interacts with T cells bearing the Vβ3, -7, or -8 T-cell receptors, inducing their expansion and cytokine secretion, leading to death in some cases due to cytokine poisoning. The majority of NKT cells bear the Vβ7 or -8 T-cell receptor, suggesting that they may play a role in regulating this response. Using mice lacking NKT cells (CD1d−/− and Jα18−/− mice), we set out to identify the role of these cells in T-cell expansion, cytokine secretion, and toxicity induced by exposure to SEB. We find that Vβ8+ CD4+ T-cell populations similarly expand in wild-type (WT) and NKT cell-null mice and that NKT cells did not regulate the secretion of IL-2. By contrast, these cells positively regulated the secretion of IL-4 and IFN-γ production and negatively regulated the secretion of tumor necrosis factor alpha (TNF-α). However, this negative regulation of TNF-α secretion by NKT cells provides only a minor protective effect on SEB-mediated shock in WT mice compared to mice lacking NKT cells. These data suggest that NKT cells may regulate the nature of the cytokine response to exposure to the superantigen SEB and may act as regulatory T cells during exposure to this superantigen.

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Mycobacterium bovis BCG-Infected Mice Are More Susceptible to Staphylococcal Enterotoxin B-Mediated Toxic Shock than Uninfected Mice despite Reduced In Vitro Splenocyte Responses to Superantigens

Infection and Immunity ◽

10.1128/iai.70.8.4148-4157.2002 ◽

2002 ◽

Vol 70 (8) ◽

pp. 4148-4157 ◽

Cited By ~ 3

Author(s):

João A. Pedras-Vasconcelos ◽

Yvan Chapdelaine ◽

Renu Dudani ◽

Henk van Faassen ◽

Dean K. Smith ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mycobacterium Bovis ◽

Staphylococcal Enterotoxin ◽

Staphylococcal Enterotoxin B ◽

Strong Type ◽

Ifn Γ ◽

Enterotoxin B

ABSTRACT Type 1 T-cell responses against intracellular pathogens play a crucial role in mediating protection. We examined whether the induction of a strong type 1 T-cell response during a chronic bacterial infection influences responses to superantigens capable of inducing acute shock. Intravenous infection of mice with Mycobacterium bovis BCG appeared to induce a progressive anergy towards staphylococcal enterotoxin B (SEB) and towards antigen preparation of BCG (BCG-Ag) itself, based on diminished gamma interferon (IFN-γ) production by SEB- and BCG-Ag-stimulated splenocytes from infected mice. In contrast to these in vitro results, injection of SEB into BCG-infected mice led to a dramatic increase in the serum IFN-γ levels and the death of infected but not of control mice. In vitro hyporesponsiveness towards SEB and BCG-Ag occurred only with unfractionated splenocyte cultures, as purified T cells from infected mice produced higher levels of IFN-γ. Hyporesponsiveness towards SEB and BCG-Ag in unfractionated splenocyte cultures was not due to suppressive antigen-presenting cells (APCs), as APCs from infected mice stimulated higher levels of IFN-γ from purified T cells. The diminished IFN-γ levels observed with bulk splenocytes appear to be due to changes in the T-cell-to-APC ratio that result in a decreased proportion of T cells, coupled to reduced proliferative responses and an increased susceptibility of effector T cells to activation-induced cell death in vitro. Our results indicate that the reported phenomena of T-cell anergy during mycobacterial infection may be an in vitro consequence of the development of a strong type 1 response in vivo.

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Bacterial superantigen, staphylococcal enterotoxin B (SEB) induces the synthesis of ICAM-1 molecules on IFN-γ treated human keratinocytes via mobilizing intracellular calcium following SEB binding to HLA-DR molecules

Journal of Dermatological Science ◽

10.1016/0923-1811(94)90393-x ◽

1994 ◽

Vol 8 (1) ◽

pp. 66

Author(s):

H. Wakita ◽

Y. Tokura ◽

F. Furukawa ◽

M. Takigawa

Keyword(s):

Intracellular Calcium ◽

Human Keratinocytes ◽

Staphylococcal Enterotoxin ◽

Staphylococcal Enterotoxin B ◽

Hla Dr ◽

Ifn Γ ◽

Enterotoxin B ◽

Bacterial Superantigen

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Staphylococcal Enterotoxin B Primes Cytokine Secretion and Lytic Activity in Response to Native Bacterial Antigens

Infection and Immunity ◽

10.1128/iai.66.11.5082-5088.1998 ◽

1998 ◽

Vol 66 (11) ◽

pp. 5082-5088 ◽

Cited By ~ 4

Author(s):

Kevin M. Mason ◽

Tricia D. Dryden ◽

Nancy J. Bigley ◽

Pamela S. Fink

Keyword(s):

Immune Cells ◽

Cytokine Production ◽

Staphylococcal Enterotoxin ◽

Interleukin 12 ◽

Staphylococcal Enterotoxin B ◽

Permeable Membrane ◽

Bacterial Antigens ◽

Ifn Γ ◽

Enterotoxin B

ABSTRACT Superantigens stimulate T-lymphocyte proliferation and cytokine production, but the effects of superantigen exposure on cell function within a complex, highly regulated immune response remain to be determined. In this study, we demonstrate that superantigen exposure significantly alters the murine host response to bacterial antigens in an in vitro coculture system. Two days after exposure to the superantigen staphylococcal enterotoxin B, splenocytes cultured withStreptococcus mutans produced significantly greater amounts of gamma interferon (IFN-γ) and interleukin-12 than did sham-injected controls. The majority of IFN-γ production appeared to be CD8+ T-cell derived since depletion of this cell type dramatically reduced the levels of IFN-γ. To study host cell damage that may occur following superantigen exposure, we analyzed cytotoxicity to “bystander” fibroblast cells cultured with splenocytes in the presence of bacterial antigens. Prior host exposure to staphylococcal enterotoxin B significantly enhanced fibroblast cytotoxicity in the presence of bacteria. Neutralization of IFN-γ decreased the amount of cytotoxicity observed. However, a greater reduction was evident when splenocyte-bacterium cocultures were separated from the bystander cell monolayer via a permeable membrane support. Increased cytotoxicity appears to be primarily dependent upon cell-cell contact. Collectively, these data indicate that overproduction of inflammatory cytokines may alter the activity of cytotoxic immune cells. Superantigen exposure exacerbates cytokine production and lytic cell activity when immune cells encounter bacteria in vitro and comparable activities could possibly occur in vivo.

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