Interleukin 6 (IL-6) Deficiency Delays Lupus Nephritis in MRL-<i>Fas<sup>lpr</sup></i>Mice: The IL-6 Pathway as a New Therapeutic Target in Treatment of Autoimmune Kidney Disease in Systemic Lupus Erythematosus

Cash, Hannes; Relle, Manfred; Menke, Julia; Brochhausen, Christoph; Jones, Simon A.; Topley, Nicholas; Galle, Peter R.; Schwarting, Andreas

doi:10.3899/jrheum.090194

Cited by 145 publications

(116 citation statements)

References 53 publications

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“…To date, most of the JAK-targeting activities have been centered on rheumatoid arthritis, psoriasis, myeloproliferative diseases, and cancer (41)(42)(43)(44)(45). Targeting cytokine/growth factor pathways important for plasma cell generation and SLE development is supported by the literature, and targeting the IL-6 pathway and receptor for SLE treatment is currently being tested (13,46,47). Targeting of the BAFF pathway has been successful, and studies in the field are under way to look at the role of APRIL in plasma cell generation (48).…”

Section: Discussionmentioning

confidence: 94%

“…Most important is the role of IL-6 as this cytokine has been implicated in multiple autoimmune diseases and directly contributes to plasma cell survival in bone marrow niches (10). In addition, multiple studies in mouse models of SLE have repeatedly demonstrated the importance of IL-6 in driving SLE disease manifestations (3,7,(11)(12)(13). Plasmablasts, precursors of plasma cells, require both APRIL and IL-6, and to a lesser degree BAFF, for full terminal differentiation to bone marrow-derived long-lived plasma cells (LL-PCs) (10,14).…”

mentioning

confidence: 99%

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Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Lu¹,

Stump²,

Wallace³

et al. 2011

The Journal of Immunology

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Accumulating evidence suggests that autoreactive plasma cells play an important role in systemic lupus erythematosus (SLE). In addition, several proinflammatory cytokines promote autoreactive B cell maturation and autoantibody production. Hence, therapeutic targeting of such cytokine pathways using a selective JAK2 inhibitor, CEP-33779 (JAK2 enzyme IC50 = 1.3 nM; JAK3 enzyme IC50/JAK2 enzyme IC50 = 65-fold), was tested in two mouse models of SLE. Age-matched, MRL/lpr or BWF1 mice with established SLE or lupus nephritis, respectively, were treated orally with CEP-33779 at 30 mg/kg (MRL/lpr), 55 mg/kg or 100 mg/kg (MRL/lpr and BWF1). Studies included reference standard, dexamethasone (1.5 mg/kg; MRL/lpr), and cyclophosphamide (50 mg/kg; MRL/lpr and BWF1). Treatment with CEP-33779 extended survival and reduced splenomegaly/lymphomegaly. Several serum cytokines were significantly decreased upon treatment including IL-12, IL-17A, IFN-α, IL-1β, and TNF-α. Anti-nuclear Abs and frequencies of autoantigen-specific, Ab-secreting cells declined upon CEP-33779 treatment. Increased serum complement levels were associated with reduced renal JAK2 activity, histopathology, and spleen CD138+ plasma cells. The selective JAK2 inhibitor CEP-33779 was able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. These data support the possibility of using potent, orally active, small-molecule inhibitors of JAK2 to treat the debilitative disease SLE.

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Lu¹,

Stump²,

Wallace³

et al. 2011

The Journal of Immunology

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“…Intrinsic renal cells produce IL-6, and this can be enhanced by anti-DNA antibodies (73). In lupus-prone mice, IL-6 exacerbates GN while inhibiting IL-6 signaling attenuated GN and reducing autoimmunity, therefore enhancing survival (74). Most IL-6 inhibition trials have occurred in RA while data are emerging in SLE.…”

Section: Autoimmune Crescentic Glomerulonephritis Lupus Nephritismentioning

confidence: 99%

Cytokines

Holdsworth

Gan

2015

Clinical Journal of the American Society of Nephrology

118

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Cytokines play an important role in host defense against microorganisms. They orchestrate innate immunity by inducing protective local inflammation and systemic acute phase responses. Cytokines are important in initiating, amplifying, directing, mediating, and regulating adaptive immunity. Unfortunately, they may also direct tissue damage if excessive responses occur or if they are involved in directing and mediating autoimmunity. Under these circumstances, cytokines are potential therapeutic targets. Over the last 20 years, we have seen the successful development and clinical implementation of biologic strategies that target key cytokines in specific inflammatory diseases with efficacy, specificity, and toxicity profiles challenging conventional drug therapies. These therapies are finding new applications and many new agents show promise. Unfortunately, these new cytokine-based therapies have had little effect on renal disease. This review provides evidence that common renal diseases, including those causing AKI and the autoimmune proliferative and crescentic forms of GN, have cytokine mediation profiles that suggest they would be susceptible to cytokine-targeting therapeutic strategies.

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“…30 Much later, a study in IL-6-deficient mice confirmed these findings in the same model. 31 In a second model of SLE, three studies supported proinflammatory effects of IL-6. First, recombinant IL-6 aggravated pathogenic immune responses and the clinical course of SLE in NZW3NZB mice.…”

mentioning

confidence: 99%

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

Luig¹,

Kluger²,

Goerke³

et al. 2015

Journal of the American Society of Nephrology

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IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Ra, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6 2/2 mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.

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Interleukin 6 (IL-6) Deficiency Delays Lupus Nephritis in MRL-Fas^lprMice: The IL-6 Pathway as a New Therapeutic Target in Treatment of Autoimmune Kidney Disease in Systemic Lupus Erythematosus

Abstract: IL-6 is a strong promoter of lupus nephritis and may be a promising new therapeutic target in the treatment of human lupus nephritis.

Cited by 145 publications

References 53 publications

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Cytokines

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

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Interleukin 6 (IL-6) Deficiency Delays Lupus Nephritis in MRL-FaslprMice: The IL-6 Pathway as a New Therapeutic Target in Treatment of Autoimmune Kidney Disease in Systemic Lupus Erythematosus

Abstract: IL-6 is a strong promoter of lupus nephritis and may be a promising new therapeutic target in the treatment of human lupus nephritis.

Cited by 145 publications

References 53 publications

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Cytokines

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

Contact Info

Product

Resources

About

Interleukin 6 (IL-6) Deficiency Delays Lupus Nephritis in MRL-Fas^lprMice: The IL-6 Pathway as a New Therapeutic Target in Treatment of Autoimmune Kidney Disease in Systemic Lupus Erythematosus