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 γ (IFN-γ) production. We examined whether direct stimulation of T cells with TLR2, 4, 5 and 7 agonists modulates CD3-mediated T-cell IL-2/IFN-γ 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-γ by T cells, the TLR2 agonist alone induced IFN-γ 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-γ 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-γ. p38 and ERK inhibitors also abolished TLR2-mediated T-cell IFN-γ. Together, our findings suggest that TLR2 directly modulates T-cell IFN-γ 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-γ release following EtOH and burn injury.
Highlights
Alcohol remains the most abused substance worldwide
Studies from our laboratory suggest that acute EtOH intoxication combined with burn injury suppresses mesenteric lymph node (MLN) T-cell proliferation as well as interleukin-2 (IL-2) and interferon γ (IFN-γ) production
Our results indicate that in conjunction with CD3 stimulation, several toll-like receptors (TLRs) ligands enhance T-cell IFN-γ production following EtOH intoxication and burn injury, a response that does not require the presence of antigen presenting cells (APCs)
Summary
Alcohol remains the most abused substance worldwide It is a high risk factor for traumatic injury, including burns [1,2,3]. The combined insult of EtOH and burn injury suppresses T-cell responses, potentiates inflammatory cytokine and chemokine production and induces neutrophil recruitment to the intestine and other organs [12,13,14]. Studies from our laboratory suggest that acute EtOH intoxication combined with burn injury suppresses mesenteric lymph node (MLN) T-cell proliferation as well as interleukin-2 (IL-2) and interferon γ (IFN-γ) production. This effect is accompanied by an increase in bacterial translocation to MLN. We have demonstrated a role for p38 and extracellular signal-regulated kinase (ERK) activation in T-cell suppression following EtOH and burn injury [15,16,17]
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