Interleukin-10, Plasma

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).

IL-10 is an anti-inflammatory cytokine that inhibits the activity of a number of cells involved in pathogen clearance including T_H1 cells, NK cells and macrophages.^3-7 Secretion of IL-10 can directly limit effector T cell responses, and it can also indirectly suppress T cell responses by limiting the antigen presenting capacity of antigen presenting cells.^8,9 IL-10 inhibits the expression of many proinflammatory cytokines, chemokines and chemokine receptors.³ It causes inhibition of IL-2 and interferon gamma. It decreases the antigen presentation and MHC class II expression of dendritic cells and co-stimulatory molecules on macrophages, and it also downregulates pathogenic T_H17 cell responses. It inhibits IL-12 production by macrophages.⁵ In contrast to its inhibitory effects on T cells, IL-10 promotes the survival, proliferation and differentiation of human B cells and increases IgG4 production.³ IL-10 causes inhibition of IL-2 and interferon gamma. A number of different types of cells can produce IL-10 including monocytes, T cells (mainly type 1 Treg cells),⁸ B cells (mainly Breg cells), a small fraction of NK cells, macrophages and dendritic cells. The predominant source of IL-10 varies in different tissues and can differ in acute or chronic stages of the infection.^5,6

IL-10 plays a significant role in immune suppression in allergen immunotherapy.^3,10,11 This cytokine is thought to mediate allergen tolerance in allergen immunotherapy and in individuals with exposure to high doses of allergens, such as beekeepers and cat owners.^12,13 Elevated serum IL-10 levels have been associated with lower subsequent risks of worsening asthma control and attacks in adults.^14,15 Elevated levels of IL-10 have been observed in the blood of patients with chronic spontaneous urticaria (CSU) compared with healthy controls.¹⁶ Subgroup analyses has revealed higher levels of IL-10 in acute versus chronic urticaria.¹⁶ Higher levels of IL-10 have been observed in autologous serum skin test (ASST) positive versus ASST–negative CSU.¹⁶ In subjects with systemic mastocytosis, the number of mast cells is elevated many fold.^3,17 Mast cells produce IL-10 add peak levels in patients with severe mast cell activation events can be elevated as much as seven-fold above baseline.^18,19 IL-10 has been associated with various events in rheumatoid arthritis, such as hyperplasia of synoviocytes, inflammatory cell infiltration and bone tissue destruction.²⁰ IL-10 also plays a role in bone metabolic diseases and in fracture healing by regulating osteogenesis.²⁰ IL-10 has been shown to regulate the growth of the giant cell tumor of the bone (GCTB) and osteosarcoma.²⁰

IL-10 elevation is a common finding in patients with hyperinflammation syndromes.^21-23 Hyperinflammation is a life-threatening pathologic state associated with a constellation of clinical disorders, including haemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome, severe coronavirus disease 2019 (COVID-19), sepsis and cytokine release syndrome.^21-23 Although these disease entities have differential etiological factors, they share a significant number of clinical symptoms, such as fever, hepatosplenomegaly, hepatitis, cytopenia, hyperferritinemia and multiorgan failure. The collection of these manifestations is also described as cytokine storm syndrome.²³ Recent studies suggest inflammatory cell death–mediated cytokine release is crucial in mediating the inflammation and tissue damage in this syndrome.²¹

Studies have shown that serum levels of IL-10 in patients with severe COVID-19 infection with cytokine storm can be markedly elevated.^24-26 A longitudinal study of COVID-19 infection found that an elevation of IL-10 is an early event—one preceding the elevations of other cytokine storm-associated proinflammatory cytokines.²⁵ It has also been shown that COVID-19 patients admitted to the intensive care unit (ICU) have significantly elevated serum levels of IL-10 relative other non-ICU COVID-19 patients.^24,27 A meta-analysis of results from a number of studies found that IL-10 can be an effective criterion for discerning the severity and predicting the course of the disease in patients with COVID-19.²⁸ Several studies suggest that the production and increase of IL-10 during COVID-19 can play a detrimental pathological role, especially during hyperinflammatory periods.²⁹

IL-10 has historically be classified as an anti-inflammatory cytokine with immunosuppressive effects.²¹ As a result, the marked elevation of IL-10 during hyperinflammation has long been interpreted as a protective mechanism to dampen the over-activated proinflammatory reactions and prevent damage to the host.²¹ However, recent studies suggest that a high IL-10 level may also be an unfavorable prognostic factor in both HLH^29,30 and severe COVID-19.^25,31 These lines of evidence, along with findings supporting proinflammatory activities of IL-10, have led to speculation that IL-10 may play a pathologic role in hyperinflammatory conditions.^29,32