Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy.
Dendritic cells (DCs) represent a small and heterogeneous fraction of the hematopoietic system, specialized in antigen capture, processing, and presentation. The different DC subsets act as sentinels throughout the body and perform a key role in the induction of immunogenic as well as tolerogenic immune responses. Because of their limited lifespan, continuous replenishment of DC is required. Whereas the importance of GM-CSF in regulating DC homeostasis has long been underestimated, this cytokine is currently considered a critical factor for DC development under both steady-state and inflammatory conditions. Regulation of cellular actions by GM-CSF depends on the activation of intracellular signaling modules, including JAK/STAT, MAPK, PI3K, and canonical NF-κB. By directing the activity of transcription factors and other cellular effector proteins, these pathways influence differentiation, survival and/or proliferation of uncommitted hematopoietic progenitors, and DC subset-specific precursors, thereby contributing to specific aspects of DC subset development. The specific intracellular events resulting from GM-CSF-induced signaling provide a molecular explanation for GM-CSF-dependent subset distribution as well as clues to the specific characteristics and functions of GM-CSF-differentiated DCs compared with DCs generated by fms-related tyrosine kinase 3 ligand. This knowledge can be used to identify therapeutic targets to improve GM-CSF-dependent DC-based strategies to regulate immunity.
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Lianne
L
van de Laar
Paul J
PJ
Coffer
Andrea M
AM
Woltman
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000235:genetics; D007167:Immunotherapy / Q000379:methods*; D008954:Models, Biological
D016178:Granulocyte-Macrophage Colony-Stimulating Factor