IL-6 in Inflammation, Immunity, and Disease

Tanaka, Toshio; Narazaki, Masashi; Kishimoto, Tadamitsu

doi:10.1101/cshperspect.a016295

Cited by 3,560 publications

(2,735 citation statements)

References 126 publications

(113 reference statements)

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“…1 and 2). IL6 is an inflammatory cytokine involved in various biologic processes, including dysimmune diseases and cancers (2,3). It is produced by many cell lineages, including stromal cells, hematopoietic cells, epithelial cells, or muscle cells.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 as a Therapeutic Target

Rossi

Liu²,

Jourdan

et al. 2015

Clinical Cancer Research

318

277

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Human IL6 is a cytokine produced by many cell types that has pleiotropic effects. In agreement, anti-IL6 therapy reduces inflammation, hepatic acute phase proteins, and anemia and has antiangiogenic effects. Blocking IL6 has demonstrated therapeutic efficacy with drug registration in Castleman disease and inflammatory diseases (rheumatoid arthritis) without major toxicity. Interestingly, the inhibition of C-reactive protein (CRP) production is a trustworthy surrogate marker of anti-IL6 therapy efficacy. Clinically registered IL6 inhibitors include siltuximab, an anti-IL6 mAb, and tocilizumab, an anti-IL6R mAb. In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL6 inhibitors, despite a full inhibition of CRP production in treated patients in vivo, the numerous data showing an involvement of IL6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in vivo. A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL6. In addition, current therapeutic strategies used in these cancers already target IL6 activity. Thus, anti-IL6 therapeutics are able to neutralize IL6 production in vivo and are safe and useful in inflammatory diseases and Castleman disease.

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Section: Introductionmentioning

confidence: 99%

Interleukin-6 as a Therapeutic Target

Rossi

Liu²,

Jourdan

et al. 2015

Clinical Cancer Research

318

277

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“…Healthy individuals have low and rather stable systemic daytime levels of IL6 although that there are some diurnal variation (19)(20)(21). The systemic IL6 concentration may increase as a result from many different insults activating inflammation including chronic inflammatory diseases like rheumatoid arthritis (16). IL6 is also implicated in the pathophysiology of various solid tumors (17) and high IL6 levels are prognostic and correlate with tumor metastasis, disease stage, and short survival in several cancers including RCC (15).…”

Section: Discussionmentioning

confidence: 99%

“…IL6 is a pleiotropic cytokine (16)(17)(18). Healthy individuals have low and rather stable systemic daytime levels of IL6 although that there are some diurnal variation (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis

Hawkins

Gore

Shparyk

et al. 2016

Clinical Cancer Research

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Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) þ IFNa versus IFN in metastatic renal cell carcinoma (RCC).Experimental Design: In a randomized, open-label, multicenter, phase II/III study, 513 patients with RCC received Nap (15 mg/ kg i. v. in three cycles of four once-daily injections) þ IFN (9 MU s. c. three times weekly), or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS).Results: This phase II/III study did not meet its primary endpoint. Median OS/PFS for Nap þ IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (P ¼ 0.56; HR, 1.08/P ¼ 0.41; HR, 0.92). Post hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of anti-SEA/E-120 (anti-Nap antibodies) for drug exposure and IL6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n ¼ 130) having concentrations below median of anti-SEA/E-120 and IL6 benefitted greatly from the addition of Nap. In SG, median OS/PFS for the patients treated with Nap þ IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (P ¼ 0.02; HR, 0.59/P ¼ 0.02; HR, 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile.Conclusions: The study did not meet its primary endpoint. Nap þ IFN has an acceptable safety profile, and results from post hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker-defined RCC patient subgroup. The results warrant further studies with Nap in this subgroup. Clin Cancer Res; 22(13); 3172-81. Ó2016 AACR.

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“…7 Sistemik JİA'nın patogenezinde IL-6'nın büyük bir rol oynadığı gösterilmiştir. 5,8,9 İL-6'nın JİA'daki rolü ilk kez, 1998 yılında Keul ve ark.nın serum IL-6 seviyesinin sistemik JİA'da diğer alt gruplara göre daha yüksek olduğunu göstermeleri ile ortaya çıkmıştır. 10 Büyüme geriliği, JİA gibi kronik inflamasyon ile karakterize birçok hastalığın sık rastlanan bir komplikasyonudur.…”

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Interleukin-6 Concentrations and Growth Velocity in Juvenil Idiopathic Arthritis

Yıldırım¹,

Çakar²,

Kızılgün³

et al. 2015

Turkiye Klinikleri J Pediatr

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Ö ÖZ ZE ET T A Am ma aç ç: : Jüvenil idiyopatik artrit (JİA) hastalarında büyüme hızının inflamasyon bulguları, hastalık aktivasyonu, interlökin-6 (IL-6) ve tedavi ile olan ilişkisini araştırmaktır. G Ge er re eç ç v ve e Y Yö ön nt te em ml le er r: : Çalışmaya 64 JİA tanılı hasta alındı. İnaktif hastalık ve klinik remisyon kriterleri, başlangıçta ve izlem süresince Wallace ve ark.nın belirlediği kriterlere göre saptandı. Antropometrik veriler Dünya Sağ-lık Örgütü standartlarına göre değerlendirildi. Büyüme hızı (cm/6 ay), başlangıç ve altı ay sonraki öl-çümler arası farkın geçen süreye bölünmesi ile hesaplandı. Değerler kronolojik yaşa göre standart sapma (Z skoru) şeklinde ifade edildi. Z skoru -2 SD altındaki değerler düşük uzama hızı olarak tanımlandı. Eritrosit sedimentasyon hızı (ESH) ≥20 mm/saat, C-reaktif protein (CRP) ≥1 mg/dL ve serum IL-6 düzeyi ≥17 pg/mL değerleri artmış olarak değerlendirildi. Hastaların yaşları, cinsiyetleri, hastalık başlangıç yaşları, ortalama takip süreleri, hastalık alt tipleri ve aldıkları tedaviler kaydedildi. Klinik ve laboratuvar değerlendirme ilk değerlendirmeden altı ay sonra tekrarlandı. B Bu ul lg gu ul la ar r: : Otuz üç (%51,6) hasta kız, 31 (%48,4) hasta erkek cinsiyette idi. Hastalık tiplerine göre en fazla oligoartiküler JİA bulundu (n=27; %42,2). Aktif hastalık dönemlerinde ESH, CRP ve IL-6 değerleri yüksek olarak saptandı. Düşük büyüme hızı sıklığı %23,4 idi; glukokortikoid tedavisi ve uzun süreli hastalık ile iliş-kili bulundu. Serum ESH, CRP ve IL-6 düzeyleri büyüme hızı ile ilişkili bulunmadı. S So on nu uç ç: : JİA tanılı hastalarda düşük büyüme hızı sıklığı yüksektir. Hastalarımızda düşük büyüme hızı literatürle benzer şekilde bulunmuştur. Hastaların izleminde kullanılan inflamasyon parametrelerinin hâlâ önemini koruduğu, hastalığın aktivite belirteci olarak IL-6 düzeyinin de anlamlı olduğu sonucuna varılmıştır. Bu hastalarda glukokortikoid maruziyeti büyüme üzerine olumsuz etkili ana faktör gibi görünmektedir.A An na ah ht ta ar r K Ke el li im me el le er r: : Artrit, jüvenil romatoid; büyüme; interlökin-6 A AB BS ST TR RA AC CT T O Ob bj je ec ct ti iv ve e: : To evaluate associations of growth velocity with inflammatory markers, dise-ase activity, interleukin-6 (IL-6) levels and treatments in patients with juvenile idiopathic arthritis (JIA). M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : Sixty four patients with JIA participated in the study. Inactive disease and clinical remission criterias were determined at baseline assessment and during the follow up according to criteria of Wallace et al. Anthropometric data were classified according to the World Health Organization standards. Growth velocity (cm/6 months) was defined by the difference between baseline and 6 months later measures, divided by follow up time. Values was expressed as standard deviation (Z score) according to chronological age. Values below the Z score ≤-2 were considered low growth velocity. Erythrocyte sedimentation rate (ESR) ≥20 mm/h, C-reactive protein (CRP) ≥1 mg/dL...

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IL-6 in Inflammation, Immunity, and Disease

Cited by 3,560 publications

References 126 publications

Interleukin-6 as a Therapeutic Target

Interleukin-6 as a Therapeutic Target

A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis

Interleukin-6 Concentrations and Growth Velocity in Juvenil Idiopathic Arthritis

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