Molecular Immunology 38 (2001) 1187–1191 Review Stat5: an essential regulator of mast cell biology Christopher P. Shelburne a , Margaret E. McCoy b , Roland Piekorz c , Veronica V. Sexl c , Sheila R. Gillespie a , Daniel P. Bailey a , Anita Gharse a , Paria Mirmonsef a , Meredith N. Mann a , Mohit Kashyap a , Harry V. Wright a , Hey Jin Chong a , L. Andrew Bouton a , Carlos D. Ramirez a , Chris S. Lantz b , John J. Ryan a,∗ a Department of Biology, Virginia Commonwealth University, Richmond, VA 23284-2012, USA b Department of Biology, James Madison University, Harrisonburg, VA 22807, USA c Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA Received 27 December 2001; accepted 9 January 2002 Abstract Interleukin-3 (IL-3) and stem cell factor (SCF) are important mast cell growth and differentiation factors. Since both cytokines activate the transcription factor Stat5, a known regulator of proliferation and survival, we investigated the effects of Stat5 deficiency on mast cell development and survival. This article will review data presented at The Fourth International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils. The full set of data is now in preparation for publication. We find that the absence of Stat5 A and B results in a total loss of in vivo mast cell development. Bone marrow-derived mast cell (BMMC) populations can be cultured and maintained from Stat5-deficient mice in IL-3 + SCF, but not in either cytokine alone. The absence of Stat5 resulted in aberrant control of Bcl-2, Bcl-x L and cyclin A2, with increased apoptosis and delayed cell cycle progression after IL-3 or SCF stimulation. These results indicate that Stat5 A and B are critical regulators of in vitro and in vivo mast cell biology. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Cytokine; Interleukin-3; Stem cell factor; c-Kit; Apoptosis 1. Introduction Mast cell activation provides an environment in the con- nective and mucosal tissues that is conducive to chronic inflammation. This process is part of the etiology of asthma and other allergic diseases. However, recent data chal- lenges the dogma of mast cell function, demonstrating its importance to innate immunity (reviewed in Ryan and Huff, in press). These findings make our understanding of mast cell biology more important than ever. Essential aspects of mast cell biology have been eluci- dated by naturally occurring and targeted genetically-deficient rodents. These studies implicated stem cell factor (SCF) and interleukin-3 (IL-3) in rodent mast cell development (reviewed in Austen and Boyce, 2001, and in Galli and Hammel, 1994). Recently, Lantz and co-workers demon- strated that IL-3 is dispensable for mast cell development, but is required for normal mast cell expansion during im- mune responses to intestinal pathogens (Lantz et al., 1998). ∗ Corresponding author. Tel.: +1-804-828-0712; fax: +1-804-828-1562. E-mail address: jjryan@saturn.vcu.edu. (J.J. Ryan). It appears that IL-3 and SCF are important regulators of mast cell biology, but may function at different stages of mast cell development and proliferation. How these two cytokines work in concert is not fully understood. The receptors for SCF and IL-3 are quite different, but transduce signals through similar pathways, including phos- phatidylinositol 3 ′ -kinase (PI3-K), phospholipase C, protein kinase C, the Ras-MAP kinase (MAPK) cascade, Janus ki- nases (Jaks), and signal transducers and activators of tran- scription (Stats). The understanding of how these pathways contribute to mast cell biology is incomplete. Several stud- ies have partly addressed these questions through use of primary bone marrow-derived mast cell (BMMC) popu- lations or cell lines. The sum of these studies implicates PI3-K, Ras-MAPK, and Stat5 in IL-3- and SCF-induced sur- vival and/or proliferation (Gommerman and Berger, 1998; Timokhina et al., 1998; O’Farrell et al., 1996; Rosa Santos et al., 2000). A preliminary assessment of promoter and intronic ele- ments for genes known to function in survival, proliferation, or cytokine production revealed that many possess a poten- tial Stat5-binding site, designated as TTC-n3-GAA, where 0161-5890/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII:S0161-5890(02)00061-5