Table I.

Endogenous inhibitory mechanisms in asthma

Endogenous inhibitory mechanism	Cellular sources	Mediator-specific effects
Steroid hormones	•Adrenal glands and gonads	•Endogenous glucocorticoids have broad anti-inflammatory effects, mainly by binding intracellular receptors and modulating gene transcription2 •11β-HSD1 and 11β-HSD2 regulate local levels of endogenous glucocorticoids3, 4, 5, 6, 7, 8 •Testosterone decreases the number of ILC22s and inhibits airway inflammation9, 10, 11, 12, 13, 14
IL-10	•Treg cells, dendritic cells, macrophages, mast cells, eosinophils, neutrophils, B cells, and ILC210s	•Treg cells modulate the resolution of airway inflammation15, 16, 17, 18, 19, 20 •IL-10 acts on multiple cells to inhibit inflammatory pathways, including antigen presentation, eosinophil recruitment and activation, and cytokine production21, 22, 23, 24, 25, 26, 27
Prostaglandins	•Epithelial cells, endothelial cells, airway smooth muscle, and monocytes/macrophages	•PGE2 acts via the EP2 to regulates 5-lipoxygenase function and cysteinyl leukotriene production28 •PGE2 inhibits eosinophil migration and ILC2 activation and proliferation28, 29, 30, 31, 32, 33, 34, 35 •PGI2 suppresses TH2 cytokine expression, eosinophilia, and mucus production36
Lipoxins	•Epithelial cells, polymorphonuclear leukocytes, and platelets	•LXA4 promotes the resolution of inflammation and inhibits neutrophil-endothelial cell interactions37,38
Resolvins	•Epithelial cells, endothelial cells, and polymorphonuclear leukocytes	•RvE1 suppresses the nuclear translocation of NF-κB and cytokine production39 •RvE1 inhibits TH17 cell inflammation40 •RvD1 promotes allergen clearance41
Protectins	•Eosinophils	•PD1 elicits apoptotic signals in neutrophils and T cells42 •PD1 inhibits TNF-α and IFN-γ production42,43
Maresins	•Macrophages, neutrophils, and platelets	•MaR1 increases Treg cells and inhibits ILC2 cytokine production44,46 •MaR1 induces Treg formation44
GLP-1R	•GLP-1 is secreted by L cells in the gastrointestinal tract	•GLP-1R agonists reduce airway inflammation via a protein kinase A–dependent inactivation of NF-κB47 •GLP-1R agonists decrease IL-33 release, numbers of ILC2s expressing IL-5 and IL-13, and expression of type 2 cytokines48
AM	•Epithelial cells, endothelial cells, airway smooth muscle, macrophages, and parasympathetic neural cells	•AM increases cyclic AMP in airway smooth muscle49 and decreases AHR50, 51, 52, 53, 54, 55
NO	•Epithelial cells, endothelial cells, macrophages, neutrophils, and mast cells	•NO functions via the stimulation of soluble guanylate cyclase to increase the production of the secondary messenger cGMP •Low levels of endogenous S-nitrosothiols act as a bronchodilator56
CO	•Epithelial cells, endothelial cells, macrophages, and fibroblasts	•HO-1–derived CO activates cGMP and promotes airway smooth muscle relaxation57 •CO decreases the alarmin response from airway epithelial cells58 •Administration of low-dose CO can reverse AHR59

cGMP, Cyclic guanosine monophosphate; ILC2₁₀, IL-10–producing ILC2; MaR1, maresin-1; NF-κB, nuclear factor-κB; RvE1, resolvin E1.