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Secretion of IL-16 through TNFR1 and calpain-caspase signaling contributes to MRSA pneumonia.

Ahn DS, Parker D, Planet PJ, Nieto PA, Bueno SM, Prince A - Mucosal Immunol (2014)

Bottom Line: We found that interleukin-16 (IL-16), a T cell cytokine that binds CD4, is potently activated by S. aureus, specifically by protein A (SpA), and to a much greater extent than by Gram-negative pathogens or lipopolysaccharide.The production of IL-16 contributed to lung damage as neutralization of IL-16 enhanced S. aureus clearance and resulted in diminished lung pathology in S. aureus pneumonia.Our results suggest that the ability of S. aureus to activate TNFR1 and Ca(2+)/calpain signaling contribute to T cell activation and excessive inflammation in the setting of acute pneumonia.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.

ABSTRACT
Staphylococcus aureus is a major cause of severe pneumonia. Multiple mechanisms of proinflammatory signaling are activated to recruit immune cells into the airway in response to S. aureus. We found that interleukin-16 (IL-16), a T cell cytokine that binds CD4, is potently activated by S. aureus, specifically by protein A (SpA), and to a much greater extent than by Gram-negative pathogens or lipopolysaccharide. IL-16 production involved multiple signals including ligation of tumor necrosis factor receptor (TNFR) family members or epidermal growth factor receptor, both receptors for SpA and generation of Ca(2+) fluxes to activate calpains and caspase-3. Although human airway epithelial cells, vascular endothelial cells, THP-1 and Jurkat T cells released IL-16 in response to S. aureus in vitro, in a murine model of pneumonia, CD4(+) cells were the major source of IL-16 suggesting the involvement of an autocrine signaling pathway. The production of IL-16 contributed to lung damage as neutralization of IL-16 enhanced S. aureus clearance and resulted in diminished lung pathology in S. aureus pneumonia. Our results suggest that the ability of S. aureus to activate TNFR1 and Ca(2+)/calpain signaling contribute to T cell activation and excessive inflammation in the setting of acute pneumonia.

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IL-16 secretion is SpA specific in multiple cell types(a) 16HBEs, (b) HUVECs, (c) Jurkats and (d) THP-1s were infected with wt MRSA or spa mutant (MOI 100, 4h for 16HBEs, 2h for HUVECs, Jurkats and THP-1s). SpA, LPS, and TNF were added at a concentration of 0.5 μM, 10 μg/mL, and 100 μg/mL respectively. IL-16 in culture supernatants was quantified by ELISA (*p<0.05 compared to media, Student's t-test, post-hoc Dunnett's test). Graphs represent data from at least 2 independent experiments.
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Figure 2: IL-16 secretion is SpA specific in multiple cell types(a) 16HBEs, (b) HUVECs, (c) Jurkats and (d) THP-1s were infected with wt MRSA or spa mutant (MOI 100, 4h for 16HBEs, 2h for HUVECs, Jurkats and THP-1s). SpA, LPS, and TNF were added at a concentration of 0.5 μM, 10 μg/mL, and 100 μg/mL respectively. IL-16 in culture supernatants was quantified by ELISA (*p<0.05 compared to media, Student's t-test, post-hoc Dunnett's test). Graphs represent data from at least 2 independent experiments.

Mentions: The major S. aureus surface component SpA activates TNFR1 signaling10, a receptor expected to activate IL-16 processing. The ability of the WT MRSA, a spa mutant, and purified SpA to stimulate IL-16 in several cell types was compared (Figure 2). Induction of IL-16 by the spa mutant was significantly decreased as compared to MRSA in human bronchial epithelial cells (16HBEs) (p=0.028) (Figure 2a), human umbilical vein endothelial cells (HUVECs) (p=0.002) (Figure 2b) and T cells (Jurkats) (p=0.06) (Figure 2c); WT MRSA and the spa mutant stimulated similar amounts of IL-16 in monocytes (THP-1s) (Figure 2d). SpA alone induced IL-16 release from 16HBEs, HUVECs, Jurkats and THP-1s (all p<0.05 as compared to media alone). Of note, LPS and TNF failed to stimulate IL-16 secretion in any of the cell types tested, with the exception of TNF stimulated Jurkats (p<0.05 as compared to media).


Secretion of IL-16 through TNFR1 and calpain-caspase signaling contributes to MRSA pneumonia.

Ahn DS, Parker D, Planet PJ, Nieto PA, Bueno SM, Prince A - Mucosal Immunol (2014)

IL-16 secretion is SpA specific in multiple cell types(a) 16HBEs, (b) HUVECs, (c) Jurkats and (d) THP-1s were infected with wt MRSA or spa mutant (MOI 100, 4h for 16HBEs, 2h for HUVECs, Jurkats and THP-1s). SpA, LPS, and TNF were added at a concentration of 0.5 μM, 10 μg/mL, and 100 μg/mL respectively. IL-16 in culture supernatants was quantified by ELISA (*p<0.05 compared to media, Student's t-test, post-hoc Dunnett's test). Graphs represent data from at least 2 independent experiments.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4199935&req=5

Figure 2: IL-16 secretion is SpA specific in multiple cell types(a) 16HBEs, (b) HUVECs, (c) Jurkats and (d) THP-1s were infected with wt MRSA or spa mutant (MOI 100, 4h for 16HBEs, 2h for HUVECs, Jurkats and THP-1s). SpA, LPS, and TNF were added at a concentration of 0.5 μM, 10 μg/mL, and 100 μg/mL respectively. IL-16 in culture supernatants was quantified by ELISA (*p<0.05 compared to media, Student's t-test, post-hoc Dunnett's test). Graphs represent data from at least 2 independent experiments.
Mentions: The major S. aureus surface component SpA activates TNFR1 signaling10, a receptor expected to activate IL-16 processing. The ability of the WT MRSA, a spa mutant, and purified SpA to stimulate IL-16 in several cell types was compared (Figure 2). Induction of IL-16 by the spa mutant was significantly decreased as compared to MRSA in human bronchial epithelial cells (16HBEs) (p=0.028) (Figure 2a), human umbilical vein endothelial cells (HUVECs) (p=0.002) (Figure 2b) and T cells (Jurkats) (p=0.06) (Figure 2c); WT MRSA and the spa mutant stimulated similar amounts of IL-16 in monocytes (THP-1s) (Figure 2d). SpA alone induced IL-16 release from 16HBEs, HUVECs, Jurkats and THP-1s (all p<0.05 as compared to media alone). Of note, LPS and TNF failed to stimulate IL-16 secretion in any of the cell types tested, with the exception of TNF stimulated Jurkats (p<0.05 as compared to media).

Bottom Line: We found that interleukin-16 (IL-16), a T cell cytokine that binds CD4, is potently activated by S. aureus, specifically by protein A (SpA), and to a much greater extent than by Gram-negative pathogens or lipopolysaccharide.The production of IL-16 contributed to lung damage as neutralization of IL-16 enhanced S. aureus clearance and resulted in diminished lung pathology in S. aureus pneumonia.Our results suggest that the ability of S. aureus to activate TNFR1 and Ca(2+)/calpain signaling contribute to T cell activation and excessive inflammation in the setting of acute pneumonia.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.

ABSTRACT
Staphylococcus aureus is a major cause of severe pneumonia. Multiple mechanisms of proinflammatory signaling are activated to recruit immune cells into the airway in response to S. aureus. We found that interleukin-16 (IL-16), a T cell cytokine that binds CD4, is potently activated by S. aureus, specifically by protein A (SpA), and to a much greater extent than by Gram-negative pathogens or lipopolysaccharide. IL-16 production involved multiple signals including ligation of tumor necrosis factor receptor (TNFR) family members or epidermal growth factor receptor, both receptors for SpA and generation of Ca(2+) fluxes to activate calpains and caspase-3. Although human airway epithelial cells, vascular endothelial cells, THP-1 and Jurkat T cells released IL-16 in response to S. aureus in vitro, in a murine model of pneumonia, CD4(+) cells were the major source of IL-16 suggesting the involvement of an autocrine signaling pathway. The production of IL-16 contributed to lung damage as neutralization of IL-16 enhanced S. aureus clearance and resulted in diminished lung pathology in S. aureus pneumonia. Our results suggest that the ability of S. aureus to activate TNFR1 and Ca(2+)/calpain signaling contribute to T cell activation and excessive inflammation in the setting of acute pneumonia.

Show MeSH
Related in: MedlinePlus