Effect of interleukin-15 on depressed splenic dendritic cell functions following trauma-hemorrhage

Although trauma-hemorrhage (T-H) induces suppressed splenic dendritic cell (DC) maturation and antigen presentation capacity, it remains unclear whether IL-15 modulates splenic DC functions. The aim of this study therefore was to investigate the effect of IL-15 on splenic DC functions after T-H. Male C3H/HeN mice (6–8 wk old) were randomly assigned to T-H or sham operation. T-H was induced by midline laparotomy and ∼90 min of hemorrhagic shock (blood pressure 35 mmHg), followed by fluid resuscitation (4× the shed blood volume in the form of Ringer lactate). Two hours later, mice were killed, splenic DCs were isolated, and the effects of exogenous IL-15 on their costimulatory factors, major histocompatibility class II expression, ability to produce cytokines, and antigen presentation were measured. The results indicate that IL-15 production capacity of splenic DCs was reduced following T-H. Ex vivo exposure to IL-15 attenuated the suppressed production of TNF-α, IL-6, and IFN-γ from splenic DCs following T-H. In addition, expression of surface antigen studies demonstrate that exogenous IL-15 attenuated T-H-induced downregulation of the activation of DC. The suppressed splenic DC antigen presentation function following T-H was also attenuated by IL-15 treatment. Moreover, IL-15 enhanced IL-12-induced IFN-γ production and antigen presentation by splenic DCs. These data suggest that ex vivo treatment with IL-15 following T-H provides beneficial effects on splenic DCs. The depression in IL-15 production by splenic DCs could contribute to the host's enhanced susceptibility to infections following T-H.

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Trauma-hemorrhage inhibits splenic dendritic cell proinflammatory cytokine production via a mitogen-activated protein kinase process

AJP Cell Physiology ◽

10.1152/ajpcell.00494.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. C754-C764 ◽

Cited By ~ 9

Author(s):

Takashi Kawasaki ◽

Mashkoor A. Choudhry ◽

Martin G. Schwacha ◽

Satoshi Fujimi ◽

James A. Lederer ◽

...

Keyword(s):

Dendritic Cell ◽

Cytokine Production ◽

Mitogen Activated Protein Kinase ◽

Sham Operation ◽

Dc Functions ◽

Mapk Activation ◽

Midline Laparotomy ◽

Shed Blood ◽

Splenic Dendritic Cell ◽

Mitogen Activated Protein

Although splenic dendritic cell (DC) functions are markedly altered following trauma-hemorrhage, the mechanism(s) responsible for the altered DC functions remains unknown. We hypothesized that trauma-hemorrhage inhibits DC function via suppressing toll-like receptor 4 (TLR4) expression and mitogen-activated protein kinases (MAPKs). To examine this, male C3H/HeN (6–8 wk) mice were randomly assigned to sham operation or trauma-hemorrhage. Trauma-hemorrhage was induced by midline laparotomy and ∼90 min of hypotension [blood pressure (BP) 35 mmHg], followed by fluid resuscitation (4× the shed blood volume in the form of Ringer lactate). Two hours later, mice were euthanized, splenic DCs were isolated, and the changes in their MAPK activation, TLR4-MD-2 expression, and ability to produce cytokines were measured. The results indicate that trauma-hemorrhage downregulated the lipopolysaccharide (LPS)-induced MAPK activation in splenic DCs. In addition to the decrease in MAPK activation, surface expression of TLR4-MD-2 was suppressed following trauma-hemorrhage. Furthermore, LPS-induced cytokine production from splenic DCs was also suppressed following trauma-hemorrhage. These findings thus suggest that the decrease in TLR4-MD-2 and MAPK activation may contribute to the LPS hyporesponsiveness of splenic DCs following trauma-hemorrhage. Hyporesponsiveness of splenic DCs was also found after stimulation with the TLR2 agonist zymosan. Our results may thus explain the profound immunosuppression that is known to occur under those conditions.

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The Human Mesenchymal Stromal Cell-Derived Osteocyte Capacity to Modulate Dendritic Cell Functions Is Strictly Dependent on the Culture System

Journal of Immunology Research ◽

10.1155/2015/526195 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Sara Trabanelli ◽

Federico La Manna ◽

Marco Romano ◽

Valentina Salvestrini ◽

Michele Cavo ◽

...

Keyword(s):

Dendritic Cell ◽

High Capacity ◽

Host Immune System ◽

Dc Functions ◽

Routes Of Administration ◽

Cell Functions ◽

Osteogenic Cells ◽

Different Types

In vitrodifferentiation of mesenchymal stromal cells (MSC) into osteocytes (human differentiated osteogenic cells, hDOC) before implantation has been proposed to optimize bone regeneration. However, a deep characterization of the immunological properties of DOC, including their effect on dendritic cell (DC) function, is not available. DOC can be used either as cellular suspension (detached, Det-DOC) or as adherent cells implanted on scaffolds (adherent, Adh-DOC). By mimickingin vitrothese two different routes of administration, we show that both Det-DOC and Adh-DOC can modulate DC functions. Specifically, the weak downregulation of CD80 and CD86 caused by Det-DOC on DC surface results in a weak modulation of DC functions, which indeed retain a high capacity to induce T-cell proliferation and to generate CD4+CD25+Foxp3+T cells. Moreover, Det-DOC enhance the DC capacity to differentiate CD4+CD161+CD196+Th17-cells by upregulating IL-6 secretion. Conversely, Adh-DOC strongly suppress DC functions by a profound downregulation of CD80 and CD86 on DC as well as by the inhibition of TGF-βproduction. In conclusion, we demonstrate that different types of DOC cell preparation may have a different impact on the modulation of the host immune system. This finding may have relevant implications for the design of cell-based tissue-engineering strategies.

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Activation-Dependent Expression of an Interleukin-2 Transgene Mediated by Transduction with a Lentiviral Vector Enhances T Cell Functions.

Blood ◽

10.1182/blood.v104.11.5273.5273 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5273-5273

Author(s):

Qi Sun ◽

Karen Chorney ◽

Carol Stine ◽

Kenneth G. Lucas

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Lentiviral Vector ◽

Ex Vivo ◽

Interleukin 2 ◽

Immune Functions ◽

Cell Functions ◽

Genetically Engineer ◽

Ifn Γ

Abstract Adoptive T cell immunotherapy (ATCI) is an evolving strategy that explores antigen-specific T cells manipulated ex vivo as therapeutic agents. Although the concept of ATCI has been tested clinically, with success in the treatment of post-transplant EBV induced lymphoproliferative disease, one of the major obstacles hindering its application to other malignancies is the procurement of tumor-specific T cells that possess potent anti-tumor functions even in the inhibitory environment at the tumor sites. This study aims to genetically engineer enriched viral specific T cells for improved immune functions. A self-inactivating lentiviral vector (SIN) CD69p-IL2 was constructed to encode the transgene interleukin-2 (IL2) under the control of a human CD69 promoter (CD69p), and this vector was tested in ex vivo cultivated EBV-specific T cells. SIN vector allows a high degree of autonomy for the internal promoter, and CD69 expression in the T cells is closely associated with T cell activation. Experiments showed that the SIN vectors efficiently transduced EBV-specific T cells, both CD4 and CD8. Furthermore, the newly cloned CD69p exhibited a higher degree of responsiveness to physiological antigen stimulation than the early promoter from the cytomegalovirus (CMVp). In response to stimulation by EBV-infected B cells, the percentage of IL2 expressing cells was 2 fold higher for the activated CD69p-IL2 transduced T cells than the non-transduced, or the CMVp-IL2 transduced, counterparts. In correlation with the stronger IL2 expression, 3 fold more T cells expressed the anti-viral cytokine interferon-γ (IFN-γ) in the CD69p-IL2 transduced T cells than the CMVp-IL2 transduced, and the IFN-γ expression at the single cell level was 2 fold higher in the former, indicating an enhanced functionality. While the culture supernatant from the CMVp-IL2 transduced T cells contained IL2 at a concentration 2000 fold higher than the non-transduced T cells, the IL2 level in the media from the CD69p-IL2 transduced T cells was comparable to that in the control, suggesting the IL2 expression mediated by the CD69p more relevant to T cell functions than the CMVp. These results may serve as a foundation for the further development and clinical application of specific T cells engineered for enhanced immune functions.

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DEPRESSED SPLENIC DENDRITIC CELL ANTIGEN PRESENTATION FUNCTION FOLLOWING TRAUMA-HEMORRHAGE

Shock ◽

10.1097/00024382-200606001-00153 ◽

2006 ◽

Vol 25 (Supplement 1) ◽

pp. 50-51 ◽

Cited By ~ 1

Author(s):

T Kawasaki ◽

WJ Hubbard ◽

MA Choudhry ◽

MG Schwacha ◽

KI Bland ◽

...

Keyword(s):

Dendritic Cell ◽

Antigen Presentation ◽

Cell Antigen ◽

Splenic Dendritic Cell

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Trauma-hemorrhage induces depressed splenic dendritic cell functions in mice

The Journal of Immunology ◽

10.4049/jimmunol.177.12.8877-a ◽

2006 ◽

Vol 177 (12) ◽

pp. 8877.2-8877 ◽

Cited By ~ 1

Author(s):

T. Kawasaki ◽

W. J. Hubbard ◽

M. A. Choudhry ◽

M. G. Schwacha ◽

K. I. Bland ◽

...

Keyword(s):

Dendritic Cell ◽

Cell Functions ◽

Splenic Dendritic Cell

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Antigen Presentation Capacity and Cytokine Production by Murine Splenic Dendritic Cell Subsets uponSalmonellaEncounter

The Journal of Immunology ◽

10.4049/jimmunol.169.1.108 ◽

2002 ◽

Vol 169 (1) ◽

pp. 108-116 ◽

Cited By ~ 84

Author(s):

Ulf Yrlid ◽

Mary Jo Wick

Keyword(s):

Dendritic Cell ◽

Antigen Presentation ◽

Cytokine Production ◽

Splenic Dendritic Cell ◽

Dendritic Cell Subsets

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Immunomodulatory effects of dehydroepiandrosterone in proestrus female mice after trauma-hemorrhage

Journal of Applied Physiology ◽

10.1152/japplphysiol.01201.2002 ◽

2003 ◽

Vol 95 (2) ◽

pp. 529-535 ◽

Cited By ~ 32

Author(s):

Markus W. Knöferl ◽

Martin K. Angele ◽

Robert A. Catania ◽

Michael D. Diodato ◽

Kirby I. Bland ◽

...

Keyword(s):

Immune Responses ◽

Sham Operation ◽

Splenocyte Proliferation ◽

Immune Functions ◽

Shed Blood ◽

Adrenal Steroid ◽

Ifn Γ ◽

Tissue Trauma ◽

Cellular Immune ◽

Anti Inflammatory Cytokine

Studies indicate that administration of the adrenal steroid dehydroepiandrosterone (DHEA) after trauma-hemorrhage in male mice improved cellular immune functions and reduced mortality rates from subsequent sepsis. There is evidence, however, that DHEA is converted to estrogens in males and that estrogens are immunoprotective after trauma-hemorrhage (TH). In contrast, DHEA in females can be converted to testosterone that has deleterious effects on immune functions. The aim of our study, therefore, was to determine whether administration of DHEA in proestrus females after TH would deteriorate immune responses. Proestrus female C3H/HeN mice (age 7–8 wk) were subjected to laparotomy (i.e., soft tissue trauma induced) and hemorrhagic shock (35 ± 5 mmHg for 90 min) or sham operation. The mice then received DHEA (100 μ/25 g body wt) or vehicle subcutaneously followed by fluid resuscitation (4× the shed blood volume). Plasma IL-6, splenocyte proliferation, splenocyte IL-2, IL-3, IFN-γ, IL-10 release, and splenic Mφ IL-1β, IL-6, IL-10, and IL-12 release were determined 24 h after TH. Plasma IL-6 levels were significantly increased in vehicle-treated females, and DHEA administration markedly attenuated this response. In vehicle-treated females, splenocyte proliferation, IL-2, IL-3, and IFN-γ release, and splenic Mφ IL-1β, IL-6, and IL-12 release were maintained or slightly enhanced after TH. In DHEA-treated females, however, these immune functional parameters were either unaltered compared with vehicle-treated animals or even further enhanced, but surprisingly were not depressed. Moreover, DHEA reduced splenocyte and splenic Mφ anti-inflammatory cytokine (i.e., IL-10) production after TH compared with vehicle-treated females. Because DHEA further enhances the immune responsiveness in proestrus females after TH, this hormone might be a useful adjunct even in females for further enhancing immune responses and decreasing the mortality rate after trauma and severe blood loss.

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