The role of the JAK/STAT signal transduction pathway in the biology of the human eosinophil

Eosinophils are terminally differentiated effector cells of the immune system that have been implicated as major contributors to the pathogenesis of allergic asthma. Allergic inflammation is characterized by elevated eosinophil numbers and by the increased production of the cytokines interleukin 5 (IL-5) and granulocyte/macrophage-colony stimulating factor (GM-CSF). These factors control a wide variety of eosinophil activities such as recruitment to sites of inflammation, enhancing cell survival, and the production and/or release of proinflammatory and cytotoxic effector molecules.; The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signal transduction pathway is important for the cytokine responsiveness of a variety of hematopoietic cells. My thesis is centered on regulation of STAT proteins by IL-5 family cytokines, in both blood and airway eosinophils, and resulting gene expression. The central hypothesis that has propelled my research described herein is that functioning STAT proteins are critical for function and viability of eosinophils. An important way in which the JAK/STAT may affect eosinophil biology is through transcriptional processes.; I have found that STAT3 and STAT5b signaling paths are operative in IL-5- or GM-CSF-stimulated blood and airway eosinophils. Moreover, this STAT activation results in the modulation of gene expression in IL-5 or GM-CSF-treated eosinophils.; In this regard, the mRNA of the STAT5 target, CIS-1, which is a negative regulator of the JAK/STAT pathway, was induced following IL-5 or GM-CSF stimulation of eosinophils. Furthermore, I have observed that the IL-5- or GM-CSF-related STAT activity corresponds to the enhancement of STAT-dependent protein expression, namely, the cell survival-associated kinase Pim-1 and cell cycle-regulator cyclin D3.; Pim-1 has been linked to the suppression of apoptosis of hematopoietic cells by cytokines. Because the suppression of apoptosis of eosinophils by IL-5 and GM-CSF is likely a factor in the pathogenesis of asthma, the IL-5 or GM-CSF induction of Pim-1 protein could be a potential mechanism underlying the enhancement of viability by IL-5 or GM-CSF.; Moreover, although cyclin D3 is critical for cell cycle progression, eosinophils are terminally differentiated cells that do not proceed through the cell cycle, thus these data suggest that there is an alternative role(s) for cyclin D3 in eosinophil biology.