Table 1.

Brief overview of some factors involved in alcohol-modulated immunity.

Alcohol Intake	Pattern Recognition
	Species	Study	Cell Type/Organ	Major Finding	Reference
acute	human	in vitro	monocytes	↓ TLR8- and TLR4-mediated TNFα synthesis (mRNA, protein)	[26,27]
		in vitro	monocytes	↓ TLR4-dependent NFκB activation	[27]
	mouse	in vivo	liver	↓ TLR4 gene expression	[21]
		in vivo	intestine	↓ TLR4-mediated cytokine production (sepsis model)	[23]
		in vitro	microglial cells	↑ TLR4 and TLR2 mRNA at 1 h ↓ TLR4 and TLR2 mRNA at 3 h	[24]
		in vivo	macrophages	↓ TLR2, TLR4 and TLR9 induced inflammatory response mediated by p38 and ERK1/2	[25]
	rat	in vivo	intestine	↓ TLR4 sensitivity to ligands (LPS)	[22]
chronic	mouse	in vivo	liver macrophages	↑ TLR4 protein expression	[29]
		in vivo	liver	↑ all TLR mRNAs except TLR3 and TLR5 (TLR10 and TLR11 not tested) ↓ antibiotics effectiveness toward TLR mRNA expression ↓ TNFα protein level by NADPH oxidase inhibition	[29]
	NF-κB signaling
acute	human	in vitro	monocytes	↑ p50 translocation to the nucleus ↓ cytokine levels = p65/RelA	[54,55]
		in vitro	FEMX-I melanoma cells	↑ NF-κB activation	[56]
		in vitro	monocytes	↓ NF-κB activity independently on IκB α degradation	[57]
		in vitro	monocytes	↑ IRAK-M ↓ IκB α kinase activity, NF-κB DNA binding, and NF-κB driven cellular responses	[63]
	mouse	in vitro	alveolar type 2 epithelial cells	↓ CXCL5 expression ↓ p65 phosphorylation (following LPS and TNFα exposure)	[60]
		in vivo	kupffer cells	↓ IRAK-1 and LPS-mediated activation of NF-κB at 1 h in ↑ IRAK-1 and LPS-induced NF-κB activity at 24 h	[64]
	rat	in vitro	kupffer cells	↓ LPS-induced NF-κB activation ↓ TNFα mRNA and TNFα secretion	[53]
		in vivo	peritoneal macrophages	↓ NF-κB activation = LPS-induced p65 translocation	[59]
chronic	human	in vitro	monocytes	↓IRAK-M activity ↑IRAK-1 and IKK kinase levels, NF-κB DNA binding and responses ↑ ERK activation	[63]
	mouse	in vivo	kupffer cells, leukocytes, liver	↑NF-κB phosphorylation ↑ NF-κB activation	[61,62]
	Bacterial clearance
acute	human	healthy volunteers	blood	↑ serum endotoxin ↑ 16 S rDNA levels	[83]
	mouse	in vivo	peritoneal cavity + spleen; intestinal barrier, blood	↓ bacterial clearance ↑ overgrowth of bacteria, and ↑ translocation of pathogens into the bloodstream	[23,90]
	rat	in vivo	bacteria numbers in the lungs, blood	delayed lung neutrophil recruitment ↑ elevated bacterial burden, systemic dissemination to spleen, blood, and liver	[81]
chronic	human			↑ bacterial infections	[85]
	rats	in vivo	systemic, gut mucosa	↑ endotoxemia	[87]
	Cytokines
acute	human	in vitro	lung epithelial cells	↓ IL-8 and IL-6 release	[127,128]
		in vitro	monocytes	↓ TNFα release and gene expression ↑ IL-10	[27,63]
		healthy volunteers	blood	↑ TNFα after 20 minutes, followed by ↓ IL-1β after 2-5 hours	[134]
		trauma patients	blood	↓ IL-6 ↑ TNFα after 20 minutes, followed by ↓ IL-1β after 2-5 hours	[137,138]
	mouse	in vivo	blood	↓ CXCL9, IL-6 and IL-12 ↑ IL-10	[129]
		in vivo	peritoneal lavage fluid	↓ IL-15, TNFα, IL-9, IL-1β & IL-1α, IL-13, IL-17, and IL-6 ↑ IL-10 and MIP-2	[23]
		in vivo	blood, lung	↑ IL-6 and TNFα ↑ IL-6	[139,140]
		in vivo	ileal tissue	↑ IL-6, IL-1β and IL-18 protein	[141,142]
chronic	human	in vitro	monocytes	↑ TNFα = IL-10 protein level	[28,63]
		alcoholic liver disease	blood	↑ TNFα, IL-6 and IL-1	[131]
		acute alcoholic hepatitis	blood	↑ IL-8, IL-4, and IFNγ	[132]
	mouse	in vivo	liver	↑ mRNA expression of TNFα, IL-6 and IL-10 ↑ TNFα level	[29,130]
	rat	in vivo	blood	↑ IL-1, IL-10 and TNFα	[147]
		in vivo	blood	= TNFα, IL-10, IL-6 or CXCL1 without inflammatory trigger, but ↑of IL-6 and TNF upon stimulation	[148]
		in vivo	blood	↑ IL-6, MCP-1 and TNFα	[61]
	Cellular responses
acute	human	precarious ill patients	blood	↓ CRP, circulating neutrophils and neutrophilic CD64	[200]
	mouse	in vivo	wounds	↓ MPO and neutrophilic infiltration	[172]
		in vivo	leukocytes	↓ cellular recruitment ↓ adhesion molecules ICAM-1, VCAM1, and E-selectin ↓ chemokines like CXCL8, MCP-1 and RANTES	[201]
		in vivo	lung neutrophils	↓ recruitment	[207]
	rat	in vivo	isolated PMN	↑ chemotaxis and superoxide release ↓ ingestion and intracellular killing	[175]
		in vivo	isolated PMN	↓ reduced phagocytosis of virulent K. pneumoniae	[176]
chronic	mouse	in vivo	brain tissue, microglia	↑ microglia activation	[180]
		in vitro	microglia	↑ mitochondrial ROS production	[180]
		in vivo	alveolar macrophages	↓ cellular functions e.g. phagocytosis	[183,184]
		in vivo	liver	↑ E-selectin expression = expression of P-selectin, ICAM-1, and VCAM1	[184]
	rat	in vivo	isolated PMN	↓ ROS	[174]
		in vivo	systemic, gut mucosa	↑ ROS	[87]
		in vivo	liver	modulation of different steps of neutrophil infiltration	[186]
		in vivo	isolated PMN	↑ CD18 expression	[187]
	Others
acute	human	in vitro	neuroblastoma cells	↑ HMGB1 expression and release	[91]
		in vitro	macrophages	↑ IL-1β and inflammasome activation	[145]
	mice	in vivo	brain	↑ P2X7R in alcohol sensitive brain regions	[92]