Interleukin-8, Serum

Serum

0.5 mL

0.3 mL (Note: This volume does not allow for repeat testing.)

Red-top tube or gel-barrier tube

This test is used for the measurement of Interleukin-8 (IL-8) levels in serum.

This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.

Enzyme-linked immunosorbent assay (ELISA)

Cytokines are low-molecular-weight intercellular signaling molecules that are produced de novo in response to an immune stimulus.^1-3 They regulate immune cell homeostasis by mediating innate and acquired immunity and inflammation in human health and disease. They generally (although not always) act over short distances and short time spans and at very low concentrations. They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behavior. Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation and secretion of effector molecules. It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types (pleiotropy). Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. Cytokines are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines. Cytokines can also act synergistically (two or more cytokines acting together) or antagonistically (cytokines causing opposing activities).

Interleukin-8 (IL-8) is a potent neutrophil-specific chemotactic factor that is an important mediator of the immune reaction in the innate immune system response. In 2002, IL-8 was assigned the name CXCL8 by the Chemokine Nomenclature Subcommittee of the International Union of Immunological Societies.⁴ Its primary receptors were similarly renamed; (IL8 receptor, alpha to CXCR1 and IL8 receptor, beta to CXCR2). IL-8 is expressed in various cell types including neutrophils, fibroblasts, epithelial cells, hepatocytes, alveolar macrophages, airway smooth muscle cells and endothelial cells.^5-7 Endothelial cells store IL-8 in their storage vesicles, the Weibel-Palade bodies.^8,9 Increased IL-8 concentrations have been found in inflammatory sites in patients with diseases such as psoriasis, rheumatoid arthritis, respiratory syncytial virus infection, asthma and chronic obstructive pulmonary diseases.¹⁰

IL-8 mediates its biological effects through the binding to CXC chemokine receptors, CXCR1 and CXCR2, which activates a phosphorylation cascade to trigger chemotaxis and neutrophil activation as part of the inflammatory response.^11,12 It induces chemotaxis in target cells, primarily neutrophils, causing them to migrate toward the site of infection.¹³ While neutrophil granulocytes are the primary target cells of IL-8, there are a relatively wide range of cells (endothelial cells, macrophages, mast cells and keratinocytes) that respond to this chemokine. IL-8 also stimulates phagocytosis once neutrophils arrived at the site of infection. IL-8 is also known to be a potent promoter of angiogenesis.¹⁴ Another key function of the cell signaling stimulated by CXCL8 is the initiation of the oxidative burst. This process allows the buildup of proteolytic enzymes and reactive oxygen species (ROS) that are necessary to break down the epithelial basement membrane. The release of ROS and damaging enzymes is regulated to minimize host damage while carrying out it effector functions.¹³

Dysregulated signaling by IL-8 has been implicated as a possible cause of Acute Respiratory Distress Syndrome (ARDS).^15-17 Patients with pancreatitis who developed ARDS have demonstrated significantly higher serum concentrations of IL-8 expression (indicative of neutrophil activation) compared to patients without ARDS.¹⁸ Elevated levels of IL-8 have also been reported in patients with transfusion-related acute lung injury (TRALI).¹⁹

The recent world-wide pandemic of Coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a dramatic increase in patients with acute respiratory failure and ARDS, both of which are associated with increased mortality, healthcare cost and post-recovery morbidity.¹² Neutrophil activation caused by IL-8 has been implicated in the pathogenesis and progression of this disease. In patients with severe COVID-19, IL-8 is one of the main chemokines responsible for recruitment, activation and accumulation of neutrophils. Increased IL-8 levels has been associated with the development of acute kidney injury, a complication of COVID-19, and respiratory failure as shown by a reduction in PaO2/FiO2.²⁰ IL-8 has demonstrated to be significantly higher in nonsurvivors compared to survivors of COVID-19, and the dynamic change of the serum IL-8 levels has been correlated with the severity of the disease.^21-24 IL-8 serum levels have also been shown to correlate better than IL-6 levels with overall clinical disease scores.^22,25 Elevated serum levels of IL-8 have been associated with longer duration of illness in patients with severe or critical COVID-19.²⁶ IL-8 has been associated with the recruitment and activation of polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC) that inhibit the response by T-cells to SARS-CoV-2.²⁷ Additionally, the frequency of PMN-MDSCs in critical COVID-19 patients is higher in non-survivors compared with survivors, and the frequency of PMN-MDSCs is positively correlated with plasma levels of IL-8 in hospitalized COVID patients.²⁷

IL-8 has been shown to have multiple pro-tumorigenic roles within the tumor microenvironment, including stimulating proliferation or transformation of tumor cells into a migratory or mesenchymal phenotype.^28-30 Further, IL-8 can increase tumor angiogenesis or recruit larger numbers of immunosuppressive cells to the tumor.²⁸ In several malignancies, patients with higher levels of IL-8 at baseline experience worse clinical outcomes.^28,31-35 Additionally, studies have shown that the chemokine directly contributes to the development of resistance to both chemotherapy and molecularly targeted agents.²⁸ More recently, clinical studies evaluating levels of IL-8 in patients receiving immune checkpoint inhibition (ICI) therapy deduced that myeloid tumor infiltration driven by IL-8 contributes to resistance to ICI agents and that peripheral IL-8 can predict outcomes to ICI therapy.²⁸