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Objective To investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity. Methods Expression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (T-H) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26-treated human BBB ECs. Myelin oligodendrocyte glycoprotein(35-55) experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry. Results IL-26 expression was induced in T-H lymphocytes by T(H)17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4(+)IL-26(+) T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs. Conclusions Our study demonstrates that although IL-26 is preferentially expressed by T(H)17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by T(H)17 lymphocytes. This work was funded by a grant from the Canadian Institutes of Health Research (MOP136980). A. Prat holds a senior Canada Research Chair in Multiple Sclerosis. M. Charabati held a postdoctoral studentship from the Fonds de recherche du Quebec-Sante (FRQS) and is now supported by a doctoral scholarship from the Multiple Sclerosis Society of Canada (MSSC). E. Peelen and S. Zandee held a postdoctoral studentship from the FRQS/MSSC Partnership Award. B. Broux held a postdoctoral studentship from Fonds Wetenschappelijk Onderzoek-Vlaanderen. L. Hachehouche held PhD studentships from the MSSC, FRQS, and Neuroinflammation Training Program. Prat, A (corresponding author), Univ Montreal, Fac Med, Multiple Sclerosis Clin, Res Ctr,Ctr Hosp Univ Montreal CRCHUM,Dept Neuros, Montreal, PQ, Canada. a.prat@umontreal.ca

Objective Human herpesvirus 8 (HHV-8) encodes a viral interleukin 6 (vIL-6) which is structurally and functionally similar to human interleukin 6 (hIL-6). Since hIL-6 has been shown to upregulate the expression of HIV-1, the objectives of this study were to examine the ability of vIL-6 to upregulate HIV-1, and to determine the interactions of this virokine (viral cytokine) with the components of the interleukin 6 (IL-6) receptor complex. Design and methods Recombinant HHV-8 vIL-6 (rvIL-6) was assayed for bioactivity in the IL-6-dependent cell line MH60.BSF2. HIV-1 p24 production by the U1 monocytic and ACH-2 T-cell lines, which are chronically infected with HIV-1, was used to assess the ability of vIL-6 to affect HIV-1 expression. hIL-6 and vIL-6 receptor utilization was determined by quantifying HIV-1 p24 production after neutralization of components of the IL-6 receptor complex, CD126'IL-6R' and CD130'gp130', on U1 cells with blocking antibodies. Results HHV-8 rvIL-6 was seen to have IL-6-like bioactivity in MH60.BSF2 cells, and readily upregulated HIV-1 p24 production in U1 monocytic cells, but not in ACH-2 T cells. The vIL-6 appeared to utilize the IL-6-specific component of the IL-6 signaling complex, CD126'IL-6R', in U1 cells. Conclusions HHV-8 vIL-6 clearly has the potential to upregulate HIV-1 expression in monocytic cells, and therefore may play a role in AIDS pathogenesis in individuals infected with both viruses.

In view of the importance of the IL-2 receptors in the expression of antiallograft immunity and the currently existing controversy regarding the effect of CsA on the induction of IL-2 receptors, we explored the effect of cyclosporine on the induction of interleukin-2 receptor alpha and beta in normal human T cells. The effect of CsA on the induction of IL-2 receptors was examined at the levels of mRNA expression (with the aid of the polymerase chain reaction), protein (by SDS-PAGE analysis of chemically crosslinked 125I-IL-2 membrane protein complexes and by FACS), and function (by Scatchard analysis of 125I-IL-2 binding to T cells). The T cells were signaled with sn-1,2-dioctanoylglycerol and ionomycin or with crosslinked anti-CD3 and anti-CD2 mAbs. Our experimental design revealed that (A) CsA inhibits the induction of IL-2 receptor alpha and beta in normal human T cells, (B) the inhibitory activity is realized by a direct effect on T cells, and (C) the inhibitory activity is detectable at the pretranslational level--CsA significantly reduced the induction of mRNA encoding IL-2 receptor alpha and IL-2 receptor beta. These observations together persuasively demonstrate the ability of CsA to interrupt the emergence of IL-2 receptors on the surface of normal human T cells.