The cytokine network in asthma and chronic obstructive pulmonary disease

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are very common inflammatory diseases of the airways. They both cause airway narrowing and are increasing in incidence throughout the world, imposing enormous burdens on health care. Cytokines play a key role in orchestrating the chronic inflammation and structural changes of the respiratory tract in both asthma and COPD and have become important targets for the development of new therapeutic strategies in these diseases.

Figure 1. Cytokines involved in asthma.

Epithelial cells play an important role in orchestrating the inflammation of asthma through the release of multiple cytokines, including SCF (which maintains mast cells in the airways), TSLP (which acts on DCs to release the Th2 chemoattractants CCL17 and CCL22, which act via CCR4), and several chemokines that attract eosinophils by activating CCR3. Th2 cells orchestrate the inflammatory response in asthma through the release of IL-4 and IL-13 (which stimulate B cells to synthesize IgE), IL-5 (which is necessary for eosinophilic inflammation), and IL-9 (which stimulates mast cell proliferation). Mast cells are thus orchestrated by several interacting cytokines and play an important role in asthma through the release of the bronchoconstrictor mediators histamine, cysteinyl-leukotrienes (Cys-LTs), and PGD2. Adapted with permission from Nature Publishing Group (1).

Figure 2. Cytokines involved in COPD.

Inhaled irritants, such as cigarette smoke, activate epithelial cells and macrophages to release multiple cytokines, including growth factors such as TGF-β and FGFs, which stimulate fibroblast proliferation, resulting in fibrosis in the small airways. These cells also secrete the proinflammatory cytokines TNF-α, IL-1β, and IL-6, all of which amplify inflammation, and several chemokines that attract circulating cells into the lungs. CCL2 acts via CCR2 to attract monocytes (which differentiate into macrophages in the lungs); CXCL1 and CXCL8 act via CXCR2 to attract neutrophils and monocytes; and CXCL9, CXCL10, and CXCL11 act via CXCR3 to attract Th1 cells and Tc1 cells, both of which release IFN-γ, which in turn stimulates the release of more of these CXCR3-binding chemokines. Mucus hypersecretion is stimulated by EGF and TGF-α. CTGF, connective tissue growth factor. Adapted with permission from Nature Publishing Group (1).

Figure 3. Th cells in airways.

Th2 cells predominate in most patients with asthma and differentiate from uncommitted precursor T cells under the influence of IL-4. Th2 cells orchestrate allergic inflammation through the release of the Th2 cytokines IL-4, IL-5, IL-9, and IL-13. Th1 cells differentiate under the influence of IL-12 and IL-27 and suppress Th2 cells through the release of IFN-γ. Th17 cells differentiate under the influence of IL-6 and IL-23. Tregs normally suppress other Th cells through the release of TGF-β and IL-10 and may have impaired function in asthma. Each Th cell type is regulated by a specific transcription factor: T-bet for Th1 cells, GATA3 for Th2 cells, retinoic acid orphan receptor-γt (RORγt) for Th17 cells, and FOXP3 for Tregs.