Activation of toll-like receptor 2 prevents suppression of T-cell interferon gamma production by modulating p38/extracellular signal-regulated kinase pathways following alcohol and burn injury Journal Article

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Authors: Li, X; Rendon, J. L.; Akhtar, S; Choudhry, M. A.
Article Title: Activation of toll-like receptor 2 prevents suppression of T-cell interferon gamma production by modulating p38/extracellular signal-regulated kinase pathways following alcohol and burn injury
Abstract: Recent studies indicate that toll-like receptors (TLRs) are expressed on T cells and that these receptors directly or indirectly activate the adaptive immune system. We have shown previously that acute alcohol/ethanol (EtOH) intoxication combined with burn injury suppresses mesenteric lymph node (MLN) T-cell interleukin-2 (IL-2) and interferon gamma (IFN-gamma) production. We examined whether direct stimulation of T cells with TLR2, 4, 5 and 7 agonists modulates CD3-mediated T-cell IL-2/IFN-gamma release following EtOH and burn injury. Male mice were gavaged with EtOH (2.9 gm/kg) 4 h prior to receiving an ~12.5% total body surface area sham or full-thickness burn injury. Animals were killed on d 1 after injury and T cells were purified from MLN and spleens. T cells were cultured with plate-bound anti-CD3 in the presence or absence of various TLR ligands. Although TLR2, 4 and 5 agonists potentiate anti-CD3-dependent IFN-gamma by T cells, the TLR2 agonist alone induced IFN-gamma production independent of CD3 stimulation. Furthermore, T cells were treated with inhibitors of myeloid differentiation primary response protein 88 (MyD88), TIR domain-containing adaptor protein (TIRAP), p38 and/or extracellular signal-regulated kinase (ERK) to determine the mechanism by which TLR2 mediates IL-2/IFN-gamma production. IL-2 was not influenced by TLR agonists. MyD88 and TIRAP inhibitory peptides dose-dependently diminished the ability of T cells to release IFN-gamma. p38 and ERK inhibitors also abolished TLR2-mediated T-cell IFN-gamma. Together, our findings suggest that TLR2 directly modulates T-cell IFN-gamma production following EtOH and burn injury, independent of antigen-presenting cells. Furthermore, we demonstrated that MyD88/TIRAP-dependent p38/ERK activation is critical to TLR2-mediated T-cell IFN-gamma release following EtOH and burn injury.
Journal Title: Molecular medicine (Cambridge, Mass.)
Volume: 18
ISSN: 1528-3658; 1076-1551
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 982
End Page: 991
Language: eng
DOI/URL:

10.2119/molmed.2011.00513
Notes: LR: 20141016; GR: F30 AA020167/AA/NIAAA NIH HHS/United States; GR: F30AA020167/AA/NIAAA NIH HHS/United States; GR: R01AA015731/AA/NIAAA NIH HHS/United States; GR: R01AA015731-04S1/AA/NIAAA NIH HHS/United States; GR: T32AA013527/AA/NIAAA NIH HHS/United States; JID: 9501023; 0 (Interleukin-2); 0 (Membrane Glycoproteins); 0 (Myeloid Differentiation Factor 88); 0 (Protein Kinase Inhibitors); 0 (Receptors, Interleukin-1); 0 (TIRAP protein, mouse); 0 (Toll-Like Receptor 2); 82115-62-6 (Interferon-gamma); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); OID: NLM: PMC3459477; 2011/12/29 [received]; 2012/05/15 [accepted]; 2012/05/15 [aheadofprint]; epublish