title: Toll-like receptors, Notch ligands, and cytokines drive the chronicity of lung inflammation.
abstract: Current dogma supports the concept that the expression of a disease-inducing signature cytokine phenotype is important to the maintenance stage of chronic lung disorders. This cytokine phenotype has been characterized as a polarization toward type 2 cytokines, which are profibrotic and immunoregulatory. The biology of this latter activity could mechanistically explain pathogen-induced exacerbation of chronic lung inflammation, as a skewed cytokine profile in the lung alters dendritic cell function, activates fibroblasts, and facilitates a subsequent "second hit" by an infectious pathogen. In this setting, cytokine biology is also linked to Toll-like receptors (TLRs) in the maintenance of lung immunity, as the activity of this receptor-ligand system by both leukocytes and stromal cells is likely an important component of disease chronicity. The participation of dendritic cells via TLRs in chronic lung disease could facilitate communication circuits established between antigen-presenting cells and lymphocytes. Data suggest that TLR activation via myeloid differentiation factor 88 adaptor protein leads to the induction of a Notch ligand known as Delta-like-4 on dendritic cells that activate the Notch receptor on T cells, promoting a helper T-cell type 1 cytokine response. It is likely that the evolution of host defense signals designed to recognize patterns emitted from a hostile microbial environment may now be superimposed on adaptive immunity and provide the underpinning to support the maintenance of chronic lung disease.
authors: Immunology Program and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA.
authors: Tracy
authors: T
authors: Raymond
authors: Matthew
authors: M
authors: Schaller
authors: Cory M
authors: CM
authors: Hogaboam
authors: Nicholas W
authors: NW
authors: Lukacs
authors: Rosemary
authors: R
authors: Rochford
authors: Steven L
authors: SL
authors: Kunkel
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008171:Lung Diseases / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D051193:Toll-Like Receptors / Q000378:metabolism*; D014777:Virus Diseases / Q000378:metabolism
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors