Endogenous suppression of mast cell development and survival by IL-4 and IL-10.
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 Fc epsilon RI 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.
Speiran
Kelly
K
Asthma and Allergic Disease Cooperative Research Center, Department of Biology, Virginia Commonwealth University, Richmond, VA 23284-2012, USA.
Bailey
Daniel P
DP
Fernando
Josephine
J
Macey
Matthew
M
Barnstein
Brian
B
Kolawole
Motunrayo
M
Curley
Dana
D
Watowich
Stephanie S
SS
Murray
Peter J
PJ
Oskeritzian
Carole
C
Ryan
John J
JJ
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D006706:Homeostasis; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism
C412319:ETV3 protein, mouse; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D016753:Interleukin-10; D015847:Interleukin-4