Table 2.

Major cytokines, chemokines and danger signals involved in the acute stress response to sterile injury.

IL-1	IL-1 has two subtypes, IL-1α and IL-1β, and they are key mediators of sterile inflammation. IL-1β is a potent pro-inflammatory cytokine produced mainly by tissue macrophages and can directly activate nociceptive fibers, and indirectly elicit the production of prostaglandins. IL-1β upregulates neutrophil- and monocyte-endothelial adhesion interactions. During acute stress, systemic IL-1β markedly increases brain IL-1β levels in the hippocampus, prefrontal cortex and hypothalamus. IL-1 also stimulates the hypothalamic-pituitary-adrenal (HPA) axis and alters the Nucleus Tractus Solitarus (NTS) sympathetic and parasympathetic outflow during stress.
IL-6	IL-6 is a sensitive, early marker of sterile tissue damage and acts as an inducer of the acute phase protein response. It also stimulates the HPA axis during stress and is a complex multifunctional cytokine that exerts pro- and anti-inflammatory effects.
IL-8	IL-8 is a chemokine produced by monocytes, T cells, neutrophils, natural killer cells, and somatic cells (e.g., endothelial cells, fibroblasts, and epithelial cells). It is inducible by IL-1 and TNF-alpha and recruits and activates neutrophils, promotes vascular smooth muscle cell proliferation and migration, and is involved in the chemotaxic and adhesion of monocytes to endothelial cells.
IL-10	IL-10 is an anti-inflammatory cytokine that serves as a brake to hyper-inflammation and immunosuppression by reducing the synthesis of proinflammatory mediators. Adenosine via A2A receptor-CAMP/PKA pathway inhibits IL-12 and TnF-alpha and stimulates production of IL-10 by antigen-presenting cells. Other protective cytokines include IL-17 that activates the differentiation of anti-inflammatory macrophages and phagocytosis of apoptotic neutrophils in response to IL-10 or glucocorticoids, and IL-21 and IL-22 play a role against tissue inflammation and protection. Induction of IL-10 expression, and the other anti-inflammatory cytokines, is a highly desirable therapeutic goal during major surgery.
TnF-alpha	TNF-alpha serves many functions in the inflammatory response with hormonal, metabolic, hemodynamic and neural effects. The cytokine is one of the early “danger” signals produced by resident macrophages, monocytes, dendritic cells, and neutrophils and T-lymphocytes. After Injury, Schwann cells produce TNF-alpha suggesting a role in neuropathic pain. TnF-alpha is also a chemotactic factor for fibroblasts and upregulates leukocyte-endothelial adhesion interactions, and is inhibited by adenosine. TNF-alpha may alter muscle metabolism by increasing amino acid availability, and is involved in insulin resistance. It also stimulates the HPA axis during stress and has anti-inflammatory properties.
NF-κB	NF-κB is an archetypal pro-inflammatory pathway activated by IL-1 and TnF-alpha. Once activated, the pathway induces proinflammatory genes, cytokines, chemokines, and endothelial adhesion molecules. NF-κB was once considered the “holy grail” as a target for new anti-inflammatory drugs, but it is now known to have anti-inflammatory properties. Thus NF-KB transcription factors regulate inflammation and orchestrate the immune response during sterile injury or following infection.
HMGB1	High mobility group box-1 is a ubiquitous nuclear protein loosely bound to chromatin and is released from macrophages and monocytes exposed to inflammatory cytokines. It also acts as a danger signal (DAMP) from sterile injury via loss of membrane integrity of damaged or necrotic cells and is an initiator of innate immunity. HMGB1’s surface receptor, RAGE (receptor for advanced glycation end products) promotes NF-κB activation, which is responsible for most events elicited by necrotic cells. HMGB1 may also be involved in restorative effects leading to tissue repair and regeneration. Active HMGB1 secretion also appears to be under autonomic nervous control with splenic macrophages being an abundant plasma source during the stress response. After major surgery, high plasma levels have been linked to cognitive decline.
Mitochondria	Mitochondrial damage is a rich source of danger signals (DAMPS), including mitochondrial DNA, formyl peptides, cytochrome C, and ATP. These micro-particles are potent stimulators of acute inflammation. Tissue ischemia and reperfusion can also activate complement by exposing mitochondrial proteins and cell phospholipids that are recognized by natural and locally occurring antibodies and autoantibodies.