IFN-γ-Dependent and -Independent Mechanisms in Adverse Effects Caused by Concomitant Administration of IL-18 and IL-12

Nakamura, Shuji; Otani, Takeshi; Ijiri, Yoshihiro; Motoda, Ryuichi; Kurimoto, Masashi; Orita, Kunzo

doi:10.4049/jimmunol.164.6.3330

Cited by 102 publications

(73 citation statements)

References 41 publications

(26 reference statements)

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“…However, caution with respect to the use of these cytokines in the post transplant setting is warranted, as they play significant roles in acute GVHD 91 and have been shown to exacerbate GVHD in allogeneic Tcell replete BMT recipients. 223,225 Moreover, combinations of these cytokines (IL-12, -15, and -18) have been shown to exacerbate inflammatory responses 226,227 and could further promote harmful alloimmune responses and mortality in the HSCT recipient. 228 Soluble factors targeting cellular function might also be used to ameliorate immune dysfunction such as replacing a deficient cellular response directed against residual tumor or infection.…”

Section: Soluble Factors and Their Targetsmentioning

confidence: 99%

Immune restoration following hematopoietic stem cell transplantation: an evolving target

Auletta

Lazarus

2005

Bone Marrow Transplant

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Summary:Hematopoietic stem cell transplantation (HSCT) is the definitive cure for many malignant and nonmalignant diseases. However, delays in immune reconstitution (IR) following HSCT significantly limit the success of transplantation and increase the risk for infection and disease relapse in the transplant recipient. Therefore, ways to measure and to manipulate immune recovery following HSCT are emerging and their success depends directly upon an enhanced understanding for the underlying mechanisms responsible for reconstituted immunity and hematopoiesis. Recent discoveries in the activation, function, and regulation of dendritic cell (DC), natural killer (NK) cell, and T-lymphocyte subtypes have been critical in developing immunotherapies used to prevent graft-versushost disease and to enhance graft-versus-leukemia. For example, regulatory T cells that induce tolerance and NK receptor-tumor ligand disparities that result in tumor lysis are being used to minimize GVHD and tumor burden, respectively. Furthermore, expansion and modulation of immune effector cells are being used to augment hematopoietic and immune recovery and to decrease transplantrelated toxicity in the transplant recipient. Specifically, DC expansion and incorporation into antitumor and antimicrobial vaccines is fast approaching application into clinical trials. This paper will review our current understanding for IR following HSCT and the novel ways in which to restore immune function and decrease transplantrelated toxicity in the transplant recipient. Bone Marrow Transplantation (2005) 35, 835-857.

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Section: Soluble Factors and Their Targetsmentioning

confidence: 99%

Immune restoration following hematopoietic stem cell transplantation: an evolving target

Auletta

Lazarus

2005

Bone Marrow Transplant

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“…These changes were associated with high levels of IFN-␥ and other cytokines. Neutralization of IFN-␥ or the use of IFN-␥-deficient mice protected from the toxicity of the IL-12 and IL-18 mixture (32,33).In the present study we investigated the effect of dosing mice with two injections of IL-12 plus IL-18 on pancreatic inflammation and the influence of leptin as well as obesity. We demonstrate that obesity associated with leptin deficiency enhances sensitivity to the toxic effects of the IL-12 plus IL-18 combination on the pancreas and that obesity per se rather than leptin deficiency seems to account for the increased severity of AP observed in leptindeficient ob/ob mice.…”

mentioning

confidence: 99%

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Sennello¹,

Fayad²,

Pini³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short-and long-term leptin replacement therapy. Shortterm leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.cytokines ͉ inflammation ͉ obesity ͉ pancreas A cute pancreatitis (AP) is an inflammatory disorder that ranges from interstitial edema to confluent necrosis and hemorrhage. In severe cases, progress to circulatory shock, acute lung injury, renal failure, and eventual death may occur (1). Despite some controversy, numerous studies have demonstrated that obesity is associated with increased risk of the severe form of AP and with development of life-threatening complications (2-8). However, the mechanism by which increased adiposity worsens AP remains unknown.Leptin, a protein mainly produced by adipocytes, is a critical regulator of appetite (9). Leptin exerts important regulatory effects on inflammation (10). In the context of AP, the role of leptin remains controversial. In patients with AP, a correlation between serum leptin and disease severity has been reported by some investigators but not by others (11,12). Although in animal models administration of leptin decreases AP severity (13-16), more severe disease is present in leptin-deficient ob/ob and leptin receptordeficient db/db mice as well as leptin-receptor mutant fa/fa rats (17, 18). However, the differential effect of obesity versus leptin deficiency has not been fully investigated.IL-12 and IL-18 are two proinflammatory cytokines that drive the Th1 cell response, characterized by high levels of IFN-␥ (19). Both cytokines are mainly produced by monocytes/macrophages....

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“…However, further studies are needed to determine PTX cellular targets and to shed some light on intracellular mechanisms responsible for these PTX actions, as well as to explore its effects on other IL-18-induced pro-inflammatory events, such as promotion of TNF-a synthesis and expression of adhesion molecules [45,46]. This might be important in view of the findings that IL-18/IL-12 treatment induces adverse effects through not only IFN-g-dependent, but also IFN-g-unrelated mechanisms [16]. …”

Section: Discussionmentioning

confidence: 99%

“…Recently, a role for IL-18 was proposed in the pathogenesis of endotoxin shock, since both anti-IL-18-treated and IL-18-deficient mice were less sensitive to LPS injection [14,15]. Most of the symptoms of LPS-induced shock 2 weight loss, diarrhoea, haemorrhagic colitis, splenomegaly, fatty liver and atrophic thymus 2 are also found after concomitant administration of IL-18 and IL-12 [16]. In accordance with the crucial role of IFN-g in LPS toxicity [17±19], the deleterious effect of an IL-18/IL-12 combination was partly dependent on IFN-g [16].…”

Section: Introductionmentioning

confidence: 99%

“…Most of the symptoms of LPS-induced shock 2 weight loss, diarrhoea, haemorrhagic colitis, splenomegaly, fatty liver and atrophic thymus 2 are also found after concomitant administration of IL-18 and IL-12 [16]. In accordance with the crucial role of IFN-g in LPS toxicity [17±19], the deleterious effect of an IL-18/IL-12 combination was partly dependent on IFN-g [16]. Therefore, interference with IL-18 and/or IL-12 synthesis and their IFN-g-inducing activity could be a useful strategy in the therapy of sepsis.…”

Section: Introductionmentioning

confidence: 99%

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Pentoxifylline inhibits the synthesis and IFN-γ-inducing activity of IL-18

Samardžić¹,

Janković

Stošić‐Grujičić³

et al. 2001

Clinical and Experimental Immunology

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SUMMARYThe effect of phosphodiesterase-inhibiting anti-inflammatory drug pentoxifylline (PTX) on LPS-induced IL-18 synthesis and IL-18-mediated IFN-g-induction were investigated. In a dose-dependent manner PTX inhibited production of IL-18 in LPS-treated cultures of murine spleen cells and bone marrowderived macrophages. Similarly, PTX treatment significantly reduced blood IL-18 levels and expression of spleen IL-18 mRNA in LPS-challenged mice. The inhibitory effect of PTX was specific for IL-18, since LPS-induced IL-12 p40 release was not suppressed either in splenocyte cultures or blood of LPSinjected animals. Synergistic induction of IFN-g by combined IL-12/IL-18 treatment was also inhibited by PTX in vitro and in vivo. Experiments with IL-12 pretreatment of splenocytes, followed by IL-18 stimulation, revealed that PTX suppressed both IL-12 and IL-18 signals responsible for IFN-g induction. These results suggest that interference with IL-18 synthesis and IFN-g-inducing activity might contribute to anti-inflammatory actions of PTX.

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IFN-γ-Dependent and -Independent Mechanisms in Adverse Effects Caused by Concomitant Administration of IL-18 and IL-12

Cited by 102 publications

References 41 publications

Immune restoration following hematopoietic stem cell transplantation: an evolving target

Immune restoration following hematopoietic stem cell transplantation: an evolving target

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Pentoxifylline inhibits the synthesis and IFN-γ-inducing activity of IL-18

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