Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1β and by the induction of endogenous IL-1Ra

Joosten, Leo A B,Crisan, Tania O,Azam, Tania,Cleophas, Maartje C P,Koenders, Marije I,van de Veerdonk, Frank L,Netea, Mihai G,Kim, Soohyun,Dinarello, Charles A BMJ Publishing Group Ltd 2016 Annals of the Rheumatic Diseases Vol.75 No.6

<P>Objectives In the present study, we generated a new protein, recombinant human alpha-1-anti-trypsin (AAT)-IgG1 Fc fusion protein (AAT-Fc), and evaluated its properties to suppress inflammation and interleukin (IL)-1 beta in a mouse model of gouty arthritis. Methods A combination of monosodium urate (MSU) crystals and the fatty acid C16.0 (MSU/C16.0) was injected intra-articularly into the knee to induce gouty arthritis. Joint swelling, synovial cytokine production and histopathology were determined after 4 h. AAT-Fc was evaluated for inhibition of MSU/C16.0-induced IL-1 beta release from human blood monocytes and for inhibition of extracellular IL-1 beta precursor processing. Results AAT-Fc markedly suppressed MSU/C16.0-induced joint inflammation by 85-91% (p<0.001). Ex vivo production of IL-1 beta and IL-6 from cultured synovia were similarly reduced (63% and 65%, respectively). The efficacy of 2.0 mg/kg AAT-Fc in reducing inflammation was comparable to 80 mg/kg of plasma-derived AAT. Injection of AAT-Fc into mice increased circulating levels of endogenous IL-1 receptor antagonist by fourfold. We also observed that joint swelling was reduced by 80%, cellular infiltration by 95% and synovial production of IL-1 beta by 60% in transgenic mice expressing low levels of human AAT. In vitro, AAT-Fc reduced MSU/C16.0-induced release of IL-1 beta from human blood monocytes and inhibited proteinase-3-mediated extracellular processing of the IL-1 beta precursor into active IL-1 beta. Conclusions A single low dose of AAT-Fc is highly effective in reducing joint inflammation in this model of acute gouty arthritis. Considering the long-term safety of plasma-derived AAT use in humans, subcutaneous AAT-Fc emerges as a promising therapy for gout attacks.</P>

IL-32, a proinflammatory cytokine in rheumatoid arthritis

Joosten, L. A. B.,Netea, M. G.,Kim, S.-H.,Yoon, D.-Y.,Oppers-Walgreen, B.,Radstake, T. R. D.,Barrera, P.,van de Loo, F. A. J.,Dinarello, C. A.,van den Berg, W. B. Proceedings of the National Academy of Sciences 2006 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.103 No.9

<P>IL-32 is a recently discovered cytokine that induces TNFalpha, IL-1beta, IL-6, and chemokines. We investigated whether IL-32 is expressed in the synovia of patients with rheumatoid arthritis (RA) and studied associations with disease severity and the presence of other cytokines. Immunohistochemistry revealed that IL-32 is highly expressed in RA synovial tissue biopsies, whereas IL-32 was not observed in synovial tissues from patients with osteoarthritis. Moreover, in synovial biopsies from 29 RA patients with active disease, the level of IL-32 staining correlated with erythrocyte sedimentation rate, a marker of systemic inflammation (R = 0.63 and P < 0.0003). Synovial staining of IL-32 also correlated with indices of synovial inflammation (R = 0.80 and P < 0.0001) as well as synovial presence of TNFalpha (R = 0.68 and P < 0.004), IL-1beta (R = 0.79 and P < 0.0001), and IL-18 (R = 0.82 and P < 0.001). IL-32 was a potent inducer of prostaglandin E(2) release in mouse macrophages and human blood monocytes, an important property for inflammation. After the injection of human IL-32gamma into the knee joints of naïve mice, joint swelling, with pronounced influx of inflammatory cells and cartilage damage, was observed. In TNFalpha-deficient mice, IL-32-driven joint swelling was absent and cell influx was markedly reduced, but loss of proteoglycan was unaffected, suggesting that IL-32 activity is, in part, TNFalpha-dependent. IL-32, strongly associated with TNFalpha, IL-1beta, and IL-18, appears to play a role in human RA and may be a novel target in autoimmune diseases.</P>

Prophetic Discourse and Popular Rhetoric in the Hebres Bible

Jan Joosten(얀 요스튼) 한국신학정보연구원 2013 Canon&Culture Vol.7 No.2

구약 성경의 예언적 본문에는 때때로 이해하기 힘들 정도로 복잡한 수사법이 나타난다. 부분적으로 그러한 어려움은 고대 이스라엘 사람들이 두루 사용하던 문체의 규약에 익숙하지 않은 데에서 비롯한다. 예언자의 신탁에 대한 연구는 그 문체의 일부 특징이 역사서에 보존되어 있는 기록된 화법의 표본에서도 드러나는 점을 관찰함으로써 접근 가능하다. 그 현상은 예언자의 수사법이 민간의 설득 화법 양식에 뿌리박고 있다는 것을 보여주는 경향이 있다. 일반적으로 신탁보다 기록된 화법을 더 쉽게 이해할 수 있기 때문에, 그들을 비교하여 예언자의 연설을 이해하는 데 도움을 받을 수 있다. 이 논문은 방법론적으로 예언자의 신탁과 이야기 본문에서 조성된 화법에서 발견할 수 있는 몇 가지 두드러진 화법의 특징을 간파하는 접근법을 사용한다. 그러한 공통된 특징들은 첫째, 부인되는 것은 절대적이 아니라, 상대적으로 부정된다는 것을 보여주는 ‘변증법적 부정’, 둘째, 어떤 인물이나 그의 행동을 특징짓기 위하여, 결코 하지 않은 말을 어떤 사람에게 돌리는 것으로 이루어진 ‘허위 인용’, 셋째, ‘환칭(換稱)의 호격’으로서, 그 안에서 어떤 사람이 암묵적으로 판단하는 다른 이름으로 불리는 것이다. The prophetic texts of the Old Testament exhibit a sophisticated rhetoric that is at times hard to understand. Partly the difficulty stems from lack of familiarity with the stylistic conventions current among ancient Israelites. A possible approach to the study of prophetic oracles is afforded by the also in samples of reported speech contained in the historical books. The phenomenon tends to show that prophetic rhetoric is rooted in popular modes of persuasive speech. Since the reported speeches are generally easier to understand than the oracles, the comparison throws light on prophetic oratory. The article illustrates the approach by the help of a few striking figures of speech that are found in both prophetic oracles and speeches imbricated in narrative texts: 1) the "dialectic negation" implying that what is negated is not denied absolutely but only relatively; 2) the "pseudo-quotation" that consists of attributing to someone words that were never spoken with a view to characterizing the person or his behavior. 3) the "antonomastic vocative," whereby someone is addressed by a different name expressing an implicit judgment.

Prophetic Discourse and Popular Rhetoric in the Hebrew Bible

Jan Joosten 한국신학정보연구원 2013 Canon&Culture Vol.7 No.2

The prophetic texts of the Old Testament exhibit a sophisticated rhetoric that is at times hard to understand. Partly the difficulty stems from lack of familiarity with the stylistic conventions current among ancient Israelites. A possible approach to the study of prophetic oracles is afforded by the observation that some of their stylistic features are encountered also in samples of reported speech contained in the historical books. The phenomenon tends to show that prophetic rhetoric is rooted in popular modes of persuasive speech. Since the reported speeches are generally easier to understand than the oracles, the comparison throws light on prophetic oratory. The article illustrates the approach by the help of a few striking figures of speech that are found in both prophetic oracles and speeches imbricated in narrative texts: 1) the “dialectic negation” implying that what is negated is not denied absolutely but only relatively; 2) the “pseudo-quotation” that consists of attributing to someone words that were never spoken with a view to characterizing the person or his behavior. 3) the “antonomastic vocative,” whereby someone is addressed by a different name expressing an implicit judgment.

GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain.

Eijkelkamp, Niels,Heijnen, Cobi J,Willemen, Hanneke L D M,Deumens, Ronald,Joosten, Elbert A J,Kleibeuker, Wendy,den Hartog, Ilona J M,van Velthoven, Cindy T J,Nijboer, Cora,Nassar, Mohammed A,Dorn, Ge The Society 2010 The Journal of neuroscience Vol.30 No.6

<P>Chronic pain associated with inflammation is a common clinical problem, and the underlying mechanisms have only begun to be unraveled. GRK2 regulates cellular signaling by promoting G-protein-coupled receptor (GPCR) desensitization and direct interaction with downstream kinases including p38. The aim of this study was to determine the contribution of GRK2 to regulation of inflammatory pain and to unravel the underlying mechanism. GRK2(+/-) mice with an approximately 50% reduction in GRK2 developed increased and markedly prolonged thermal hyperalgesia and mechanical allodynia after carrageenan-induced paw inflammation or after intraplantar injection of the GPCR-binding chemokine CCL3. The effect of reduced GRK2 in specific cells was investigated using Cre-Lox technology. Carrageenan- or CCL3-induced hyperalgesia was increased but not prolonged in mice with decreased GRK2 only in Na(v)1.8 nociceptors. In vitro, reduced neuronal GRK2 enhanced CCL3-induced TRPV1 sensitization. In vivo, CCL3-induced acute hyperalgesia in GRK2(+/-) mice was mediated via TRPV1. Reduced GRK2 in microglia/monocytes only was required and sufficient to transform acute carrageenan- or CCL3-induced hyperalgesia into chronic hyperalgesia. Chronic hyperalgesia in GRK2(+/-) mice was associated with ongoing microglial activation and increased phospho-p38 and tumor necrosis factor alpha (TNF-alpha) in the spinal cord. Inhibition of spinal cord microglial, p38, or TNF-alpha activity by intrathecal administration of specific inhibitors reversed ongoing hyperalgesia in GRK2(+/-) mice. Microglia/macrophage GRK2 expression was reduced in the lumbar ipsilateral spinal cord during neuropathic pain, underlining the pathophysiological relevance of microglial GRK2. Thus, we identified completely novel cell-specific roles of GRK2 in regulating acute and chronic inflammatory hyperalgesia.</P>

Mini Review : Th17 responses and host defense against microorganisms: an overview

Frank L. Van De Verrdonk,Mark S. Gresnigt,Bart Jan Kullberg,Jos W. M. Van Der Meer,Leo A. B. Joosten,Mihai G. Netea 한국생화학분자생물학회 2009 BMB Reports Vol.42 No.12