The cytokines interleukin 2 (IL-2) and IL-15 have similar biological effects on T cells and bind common hematopoietin receptor subunits. Pathways that involve Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to be important for hematopoietin receptor signaling. In this study we identify the STAT proteins activated by in human T cells. IL-2 and IL-15 rapidly induced the tyrosine phosphorylation of STAT3 and STAT5, and DNA-binding complexes containing STAT3 and STAT5 were rapidly activated by these cytokines in T cells. IL-4 induced tyrosine phosphorylation and activation of STAT3 but not STAT5. JAK1 and JAK3 were tyrosinephosphorylated in response to IL-2 and IL-S15. Hence, the JAK and STAT molecules that are activated in response to IL-2 and IL-15 are similar but differ from those induced by IL-4. These observations identify the STAT proteins activated by IL-2 and IL-15 and therefore define signaling pathways by which these T-cell growth factors may regulate gene transcription.Interleukin 2 (IL-2) is a key growth factor that induces the proliferation and functional differentiation of T lymphocytes and natural killer cells. IL-15 shares many characteristics with IL-2, such as the generation of cytotoxic T cells and lymphokine-activated killer cells (1-3). Two IL-2 receptor subunits, the , chain (p75) and the common y chain (-yc), are used by IL-15, and Yc is also shared by other cytokine receptors, including the IL-4 receptor (4, 5). Studies also suggest the existence of an IL-15 receptor subunit distinct from the IL-2 receptor subunits (3). The finding that IL-15 and IL-2 share receptor subunits and exhibit overlapping biological effects implies that they may activate common intracellular substrates but, as yet, this has not been explored.Recently, a signal transduction pathway that involves Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) has been found to be utilized by a number of growth factors and cytokines that bind members of the hematopoietin receptor family (6, 7). We and others (8-11) have cloned a member of the Janus family (JAK3) and have shown that JAK3 and JAK1 are functionally coupled to the IL-2 receptor, as well as other receptors that use 'yc (receptors for IL-4, -7, and -9). The requisite role of yc in signaling is perhaps best illustrated by the discovery that mutations of this subunit result in X chromosome-linked severe combined immunodeficiency (12). Many of these mutations disrupt JAK3-,yc interactions, suggesting that this disruption might be important in the pathogenesis of this immunodeficiency (13). Given that IL-15 shares this common receptor subunit, it was important to examine whether IL-15 might also activate JAK3 and JAK1. Studies of the mechanism by which hematopoietin receptors activate gene transcription indicate that STAT proteins become rapidly tyrosine-phosphorylated in the receptor complex and directly translocate to the nucleus, where they bind DNA and activate transcription (14...
Highlights d Host macrophages (Mf) are indispensable for BM-MSCdependent reduction of colitis d MSC-secreted chemokines CCL2 and CXCL12 synergistically induce M2 polarization d Host IL-10 competency is crucial for MSC-mediated recovery of DSS colitis d MSC-polarized host Mf regulate IL-10 polarization by gutbound lymphoid cells
Culture-adapted bone marrow mesenchymal stromal cells (MSCs) deploy paracrine anti-inflammatory and tissue regenerative functionalities that can be harnessed as a living cell pharmaceutical product. Independent of clinical indication, a near majority of human clinical trials administer MSC IV, often with an allogeneic MSC cell product immediately after thawing from cryostorage. Despite hundreds of studies in a wide assortment of inflammatory, degenerative, and acute tissue injury syndromes, human clinical outcomes often fail to mirror promising rigorously conducted preclinical animal studies. Using a mouse model of toxic colitis, we demonstrate that replication fit MSCs harvested in log phase of growth have substantial impact on colitis clinical and pathologic endpoints when delivered subcutaneously or intraperitoneally, whereas the maximum tolerated IV bolus dosing failed to do so. We also demonstrate that heat-inactivated MSCs lose all therapeutic utility and the observation is mirrored by use of viable MSC administered immediately postthaw from cryostorage. Using luciferase transgenic MSC as donor cells, we demonstrate that transient in vivo engraftment is severely compromised when MSCs are dead or thawed and further demonstrate that MSC redosing is feasible in relapsing colitis, but only syngeneic MSCs lead to sustained improvement of clinical endpoints. These data support the notion that pharmaceutical potency of MSC requires viability and functional fitness. Reciprocally, IV administration of thawed MSC products may be biased against positive clinical outcomes for treatment of colitis and that extravascular administration of syngeneic, fit MSCs allows for effect in a recurrent therapy model.
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