Endogenous suppression of mast cell development and survival by IL-4 and IL-10
Open Access
- 19 February 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 85 (5), 826-836
- https://doi.org/10.1189/jlb.0708448
Abstract
Mast cell development is an important component of atopic and chronic inflammatory diseases such as asthma, multiple sclerosis, rheumatoid arthritis, and atherosclerosis. In this study, we found that IL-4 and IL-10 were produced constitutively in cultures of developing mast cells, correlating with mast cell purity. Deletion of either gene increased mast cell numbers and FcεRI expression during culture in IL-3 + stem cell factor (SCF). By adding exogenous IL-4 and IL-10 to bone marrow (BM) cultures containing IL-3 + SCF, we found that IL-4 + IL-10 suppressed mast cell development through mechanisms not used by either cytokine alone. IL-4 + IL-10 elicited a rapid cell death coincidental with reduced Kit receptor expression and signaling and enhanced mitochondrial damage and caspase activation. IL-4 or IL-10 costimulation, unlike either cytokine alone, altered mast cell ontogeny to yield predominantly macrophages in cultures that typically produce mast cells. This effect was observed consistently with unseparated BM cells, purified mouse BM stem cells, and erythrocyte-depleted human umbilical cord blood cells. These experiments demonstrated a major role for Stat6 and Stat3, but not the Stat3-induced transcriptional repressor Ets variant gene 3. Genetic background was also a critical factor, as BALB/c-derived BM cells were completely resistant to IL-10-mediated killing and expressed lower levels of IL-10R. Collectively, these results support the theory that IL-4 and IL-10 function as endogenous regulators of mast cell progenitor development, consistent with a role in immune homeostasis. Loss of this homeostasis, perhaps via genetic polymorphism, could contribute to the etiology of mast cell-associated disease.Keywords
Funding Information
- National Institutes of Health (1R01AI59638, U191077435, K01AR053186)
- The Jeffress Trust Foundation (J-833)
This publication has 89 references indexed in Scilit:
- Polymorphisms in the interleukin 13 and GATA binding protein 3 genes and the development of eczema during childhoodBritish Journal of Dermatology, 2008
- STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophilsBlood, 2006
- Mast cells in diffuse large B‐cell lymphoma; their role in fibrosisHistopathology, 2006
- Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphomaBlood, 2004
- Atopy and asthma: genetic variants of IL-4 and IL-13 signallingImmunology Today, 2000
- IMMUNOLOGIC BASIS OF ANTIGEN-INDUCED AIRWAY HYPERRESPONSIVENESSAnnual Review of Immunology, 1999
- Serum interleukin 4 and interleukin 10 levels in patients with chronic hepatitis C virus infectionJournal of Hepatology, 1997
- A new variant of the beta subunit of the high-affinity receptor for immunoglobulin E (Fc epsilon RI-beta E237G): associations with measures of atopy and bronchial hyper-responsivenessHuman Molecular Genetics, 1996
- Stat6 Is Required for Mediating Responses to IL-4 and for the Development of Th2 CellsImmunity, 1996
- Generation and Analysis of Interleukin-4 Deficient MiceScience, 1991