Key Points BCR stimulation promotes mRNA translation in CLL cells, including of the oncoprotein, MYC, and is inhibited by ibrutinib or tamatinib. Differences in mechanisms of regulation of mRNA translation in CLL and normal blood B cells may highlight potential targets for therapy.

Although reactive glia formation after neuronal degeneration or traumatic damage is one of the hallmarks of central nervous system (CNS) injury, we have little information on the signals that direct activation of resting glia. IL-15, a pro-inflammatory cytokine involved in regulating the response of T and B cells, may be also key for the regulation of early inflammatory events in the nervous system. IL-15 was expressed in the CNS, most abundantly in cerebellum and hippocampus, mainly in astrocytes and in some projection neurons. Using a rodent model of acute inflammatory injury [lipopolysaccharide (LPS) injection], we found enhanced expression of IL-15 in both reactive astroglia and microglia, soon after CNS injury. Blockade of IL-15 activity with an antibody to the cytokine, reversed activation of both glial types, suggesting that IL-15 has a major role in the generation of gliotic tissue and in the regulation of neuroimmune responses. Because IL-15 appears to modulate the inflammatory environment acutely generated after CNS injury, regulating IL-15 expression seems a clear antiinflammatory therapy to improve the outcome of neurodegenerative diseases and CNS trauma.

IL-15 expression after CCI regulates macrophage and T-cell infiltration | 1743The IL-15 levels in the dorsal horn of the spinal cord after CCI were measured by immunohistochemistry (Fig. 2a). After CCI IL-15 increased progressively its expression in the spinal cord, reaching a maximum after 24 h and at 3 days (Fig. 2a). A detailed confocal microscopical analysis showed that 5 days after CCI, IL-15 was found in the larger processes of reactive astrocytes (GFAP-IL-15 co-expression in yellow; Fig. 2b, c, and c¢), mainly in the ipsilateral dorsal horn of the spinal cord. We also found several IL-15 positive microglial cells (IB4 staining; Fig. 2e, f and e¢).Peripheral nerve injury affected IL-15 in the spinal cord, causing a biphasic response of the cytokine, related to the spinal astroglial and microglial activation following the CCI lesion.Time-course of IL-15 expression in the sciatic nerve after CCI The IL-15 response to CCI injury was observed in the injured nerve by RT-PCR, western blotting and immunohistochemistry (Fig. 3). IL-15 mRNA and protein were constitutively found in the nerve ( Fig. 3a and b). Nerve ligature caused IL-15 over-expression between 3 and 6 h post-injury, based on both mRNA and protein levels, and was down-regulated at later times ( Fig. 3a and b). Immunohistochemical analysis of the expression of the cytokine 6 h post-CCI showed increased expression of IL-15 in the ligated regions (Fig. 3c). Between 5 and 7 days post-CCI, IL-15 expression was upregulated at both mRNA and protein levels ( Fig. 3a and b). The relative levels of IL-15 protein observed 5-7 days postlesion were substantively higher than those of mRNA, compared to the 3-6 h response. Confocal microscopy analysis showed that IL-15 was mainly located in two cell types at these post-lesion times. At 12 h post-CCI, IL-15 colocalized with the damaged axons (NF in blue and IL-15 in red; co-localization as purple labeled fibers; Fig. 3d-f), being absent from p75-positive Schwann cells (p75 in green; Fig. 3f). At later times post-lesion, IL-15 was found in macrophages infiltrating the nerve 7 days after the injury (CD68-IL-15 co-localization in yellow; Fig. 3g-j). Thus, IL-15 appears to play a relevant role in the regulation of the local inflammatory response after sciatic nerve CCI.Intraneural injection of IL-15 causes macrophage and T-cell recruitment to the sciatic nerve The previous results suggested involvement of IL-15 in the regulation of the initial inflammatory events after sciatic nerve CCI. This role was confirmed by intraneural injection of exogenous IL-15, to mimic the inflammatory reactions after CCI. Injection into the sciatic nerve of the vehicle (PBS; Fig. 4a and d) caused, 5 days later, a reduction in the macrophage recruitment response (3.1 ± 0.85 CD68-positive cells/0.1 mm 2 ; Fig. 4a-d), probably due to the tissue disturbance caused by the injection procedure. However, administration of low doses of IL-15 (5 ng; Fig. 4b), significatively increased the recruitment of macrophages (CD68-positive cells) into the scia...

Reactive glia formation is one of the hallmarks of damage to the CNS, but little information exists on the signals that direct its activation. Microglial cells are the main regulators of both innate and adaptative immune responses in the CNS. The proinflammatory cytokine IL‐15 is involved in regulating the response of T and B cells, playing a key role in regulating nervous system inflammatory events. We have used a microglial culture model of inflammation induced by LPS and IFNγ to evaluate the role of IL‐15 in the proinflammatory response. Our results indicate that IL‐15 is necessary for the reactive response, its deficiency (IL‐15‐/‐) leading to the development of a defective proinflammatory response. Blockade of IL‐15, both with blocking antibodies or with the ganglioside Neurostatin, inhibited the activation of the NFκB pathway, decreasing iNOS expression and NO production. Inhibiting IL‐15 signaling also blocked the activation of the mitogen‐activated protein kinase (MAPK) pathways ERK1/2 and p38. The major consequence of these inhibitory effects, analyzed using cytokine antibody arrays, was a severe decrease in the production of chemokines, cytokines and growth factors, like CCL17, CCL19, IL‐12, or TIMP‐1, that are essential for the development of the phenotypic changes of glial activation. In conclusion, activation of the IL‐15 system seems a necessarystep for the development of glial reactivity and the regulation of the physiology of glial cells. Modulating IL‐15 activity opens the possibility of developing new strategies to control gliotic events upon inflammatory stimulation. © 2009 Wiley‐Liss, Inc.