Published online before print February 19, 2009

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(Journal of Leukocyte Biology. 2009;85:826-836.)
© 2009 Society for Leukocyte Biology

Endogenous suppression of mast cell development and survival by IL-4 and IL-10

Kelly Speiran^*,, Daniel P. Bailey, Josephine Fernando^*,, Matthew Macey^*,, Brian Barnstein^*,, Motunrayo Kolawole^*,, Dana Curley^*,, Stephanie S. Watowich, Peter J. Murray, Carole Oskeritzian^*,|| and John J. Ryan^*,,1

^* Asthma and Allergic Disease Cooperative Research Center and Departments of
Biology and
^|| Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, USA;
Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas, USA; and
Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

¹ Correspondence: Virginia Commonwealth University, Department of Biology, Box 842012, Richmond, VA 23284-2012, USA. E-mail: jjryan{at}vcu.edu

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 FcRI 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.

Key Words: ETV3 • bone marrow • interleuken-10 • interleuken-4 • Stat3