Interleukin 6 promotes murine lupus in NZB/NZW F1 mice.

Abstract

To investigate the role of IL-6 in systemic lupus erythematosus (SLE), we selectively inhibited IL-6 in lupus-prone NZB/ NZW F1(B/W) mice by chronic administration of a rat mAb to mouse IL-6. Anti-IL-6 alone elicited an anti-rat response that blocked its biologic effects. To circumvent this problem, we rendered B/W mice tolerant to the rat mAb by administration of anti-CD4 concurrent with the first dose of anti-IL-6. Thereafter, the mice received weekly injections of anti-IL-6 alone. There were two control groups: one group received the tolerizing regimen of anti-CD4 along with a control rat IgG1 mAb (GL113) instead of anti-IL-6; the other control group received PBS. Mice that received anti-CD4 were tolerant to the rat mAb for 6 mo. Throughout this period, treatment with anti-IL-6 prevented production of anti-dsDNA, significantly reduced proteinuria, and prolonged life. Mice that received anti-IL-6 without anti-CD4 developed an immune response to the rat mAb and then developed anti-dsDNA antibodies, proteinuria, and mortality comparable with control mice. These findings establish that IL-6 promotes autoimmunity in B/W mice. They further indicate that, although mAb to IL-6 can suppress murine lupus, the development of host immunity to the mAb abrogates its beneficial effects. Finally, this is the first study to demonstrate that a brief course of anti-CD4 can induce tolerance to another therapeutic mAb, in this case an anticytokine mAb. (J. Clin. Invest. 1994. 94:585-591.)

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

“…Consistent with this model, CpG-stimulated DCs from SLE patients produced lower levels of IL-6 (48), whereas endothelial cells (49 -51), mesangial cells in the kidney (52,53), and infiltrating monocytes/macrophages (54) secrete elevated levels of IL-6. This suggests that IL-6 plays a beneficial role when released in a local microenvironment between myDCs and autoreactive B cells, but when elevated systemically, it induces inflammation, tissue destruction, and spontaneous Ig production by activated B cells (41,(55)(56)(57). Therapies aimed at neutralizing the inflammatory effects of IL-6 may have short-term benefits in treating lupus nephritis; however, they are likely to promote loss of tolerance in newly emerging B cells during innate immune activation.…”

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

“…Mice and SLE patients exhibit elevated IL-6 and inhibition of IL-6 or the IL-6 receptor decreases anti-dsDNA and proteinuria. [73][74][75] With HSP90 inhibition by GA, IL-6 expression was reduced in macrophages by preventing HSP90 from chaperoning newly transcripted cytokines. 76 HSP90 complexes with iNOS and is required for iNOS to synthesize NO.…”

Interleukin‐10 Response Abnormalities in Systemic Lupus Erythematosus

“…Increased levels of IL-10 and IL-6, as well as the associated cytokines TNF-a and GM-CSF, could enhance B-cell proliferation and differentiation [16][17][18][19]. Exogenous IL-6 has been shown to promote murine lupus, while specific monoclonal antibodies (MoAb) to IL-6 and IL-10 delay the development of this disease in NZB/W F 1 mice [20,21]. An intrinsic overproduction of these cytokines might also explain the pre-existing B-cell hyperactive state reported in family members of SLE patients, as well as in lupus patients themselves [22][23][24][25][26].…”