Statistics from Altmetric.com
Interleukin (IL)6 production by antigen-presenting dendritic cells (DCs) is integral to the differentiation of T helper cells into T helper type Th1, Th2 and Th17 subsets. However, molecular mechanisms that regulate IL6 production in DCs are yet to be elucidated. Stimulation of bone marrow-derived dendritic cells with the allergen house dust mite (HDM)—which causes asthma in humans—or the mucosal adjuvant cholera toxin promoted cell surface expression of c-Kit and its ligand, stem cell factor (SCF), resulting in sustained signalling downstream of c-Kit, prompting IL6 secretion. DCs from c-Kit mutant mice secreted smaller amounts of IL6 following HDM or cholera toxin stimulation, resulting in an inability to induce a robust Th2 or Th17 response and reduced allergic airway inflammation. In addition, expression of Jagged-2, a Notch ligand which has been associated with Th2 differentiation, is reduced in DCs lacking functional c-Kit, implying that c-Kit upregulates expression of Jagged-2 in addition to IL6. Cell signalling downstream of c-Kit is likely to involve phosphorylation of Akt via activation of phosphatidylinositol-3 kinase (PI3k), as DCs expressing a catalytically inactive form of PI3K secrete less IL6 on cholera toxin stimulation.
It is concluded that cell surface expression of c-Kit by DCs in conjunction with SCF causes extended activation of the PI3K-Akt pathway, promoting a higher IL6 expression profile in DCs which, in turn, promotes T cell differentiation towards Th2 and Th17 lineage. This may have implications for the understanding and treatment of allergic airway inflammation in asthma as downregulation of c-Kit may reduce such inflammation. Inhibition of c-Kit may also promote the efficacy of vaccines in cancer therapy by augmenting a Th1 response.
Krishnamoorthy N, Oriss TB, Paglia M, et al. Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat Med 2008;14:565–73.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.