Books by Giamila Fantuzzi
Whether classified as regulators of inflammation, metabolism, or other physiological functions, a... more Whether classified as regulators of inflammation, metabolism, or other physiological functions, a distinctive set of molecules enables the human body to convey information from one cell to another. An in-depth primer on the molecular mediators that coordinate complex bodily processes, Body Messages provides fresh insight into how biologists first identified this special class of molecules and the consequences of their discovery for modern medicine.
Focusing on proteins that regulate inflammation and metabolism—including the cytokines and adipokines at the core of her own research—Giamila Fantuzzi examines the role body messages play in the physiology of health as well as in the pathology of various illnesses. Readers are introduced to different ways of conceptualizing biomedical research and to the advantages and pitfalls associated with identifying molecules beginning with function or structure. By bringing together areas of research usually studied separately, Fantuzzi stresses the importance of investigating the body as a whole and affirms the futility of trying to separate basic from clinical research. Drawing on firsthand interviews with researchers who made major contributions to the field, Body Messages illustrates that the paths leading to scientific discovery are rarely direct, nor are they always the only routes available.
Papers by Giamila Fantuzzi
Arthritis and Rheumatism, 2009
ObjectiveCaspase 1, a known cysteine protease, is a critical component of the inflammasome. Both ... more ObjectiveCaspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro–interleukin-1β (proIL-1β), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis.Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro–interleukin-1β (proIL-1β), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis.MethodsAcute and chronic arthritis were induced in caspase 1−/− mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated.Acute and chronic arthritis were induced in caspase 1−/− mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated.ResultsSurprisingly, caspase 1−/− mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1β were comparable in caspase 1−/− mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1−/− mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1–dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1β concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction.Surprisingly, caspase 1−/− mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1β were comparable in caspase 1−/− mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1−/− mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1–dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1β concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction.ConclusionCaspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1β production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1β production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.
Eur J Immunol, 2001
IL-1 receptor antagonist (IL-1Ra) is produced by isolated human hepatocytes with characteristics ... more IL-1 receptor antagonist (IL-1Ra) is produced by isolated human hepatocytes with characteristics of an acute-phase protein. There are multiple IL-1Ra peptides, one secreted (sIL-1Ra) and three intracellular (icIL-1Ra1, 2, 3). sIL-1Ra, but not icIL-1Ra1, mRNA is transcribed by cultured human hepatocytes. In this study, we examined in vivo production of IL-1Ra by the liver in mice in two experimental models of acute-phase response, systemic lipopolysaccharide (LPS) administration and local turpentine injection. Liver sIL-1Ra expression was up-regulated in response to both types of stimulation. After LPS injection, the hepatic production of sIL-1Ra correlated with the increase in plasma IL-1Ra levels. In addition, the total amount of IL-1Ra present in the liver after LPS injection was six-and tenfold higher than in the lung and spleen. As assessed by in situ hybridization, sIL-1Ra, but not icIL-1Ra, mRNA was produced by hepatocytes in vivo after LPS injection. Using IL-6 -/mice, we demonstrated that in turpentine-induced inflammation production of IL-1Ra mRNA by the liver is regulated by IL-6. In contrast, local production of IL-1Ra is independent of IL-6. Taken together, these results indicate that IL-1Ra is produced by the liver as an acute-phase protein in vivo.
American Journal of Physiology Regulatory Integrative and Comparative Physiology, 1998
Abstract Interleukins (IL) are key mediators of the host response to infection and inflammation. ... more Abstract Interleukins (IL) are key mediators of the host response to infection and inflammation. Leptin is secreted by adipose tissue and plays an important role in the control of food intake. Administration of lipopolysaccharide (LPS), tumor necrosis factor (TNF), or ...
American Journal of Physiology Regulatory Integrative and Comparative Physiology, 2000
ABSTRACT
Immunity, 1999
An interleukin-18 binding protein (IL-18BP) was purified from urine by chromatography on IL-18 be... more An interleukin-18 binding protein (IL-18BP) was purified from urine by chromatography on IL-18 beads, sequenced, cloned, and expressed in COS7 cells. IL-18BP abolished IL-18 induction of interferon-gamma (IFNgamma), IL-8, and activation of NF-kappaB in vitro. Administration of IL-18BP to mice abrogated circulating IFNgamma following LPS. Thus, IL-18BP functions as an inhibitor of the early Th1 cytokine response. IL-18BP is constitutively expressed in the spleen, belongs to the immunoglobulin superfamily, and has limited homology to the IL-1 type II receptor. Its gene was localized on human chromosome 11q13, and no exon coding for a transmembrane domain was found in an 8.3 kb genomic sequence. Several Poxviruses encode putative proteins highly homologous to IL-18BP, suggesting that viral products may attenuate IL-18 and interfere with the cytotoxic T cell response.
Acta Physiologica Scandinavica, Sep 1, 2001
The study of cytokine-deficient mice has provided important information for a better understandin... more The study of cytokine-deficient mice has provided important information for a better understanding of inflammatory processes. In this report, the characterization of mice deficient for various components of the interleukin (IL)-1 system is reviewed. Results obtained by studying mice deficient for IL-1alpha, IL-1beta, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory protein, IL-1 receptor-associated kinase, and the IL-1beta-converting enzyme caspase-1 are summarized. Because some of the components of the IL-1 system are shared with IL-18, similarities between IL-1beta and IL-18 are also discussed.
Amyloid, Jul 6, 2009
ABSTRACT This study measured, using ELISA or bioassay methodology, fluctuation in concentration o... more ABSTRACT This study measured, using ELISA or bioassay methodology, fluctuation in concentration of the circulating cytokines tumor necrosis factor (TNF) and interleukin 6 (IL-6), and the acute phase proteins serum amyloid A (apoSAA) and C-reactive protein (CRP), in five septic patients, during a one-week period starting from the day of diagnosis. All had consistently detectable levels of circulating TNF (range of peak values, 0.6-13.6 ng/ml); two also had high IL-6 levels, while the remaining three had detectable levels only at some time points (range of peak values, 105-31j pg/ ml). TNF concentrations fluctuated during the observation period, in some cases with a biphasic temporal pattern. TNF and IL-6 levels were undetectable (below 30 and 100 pg/ml, respectively) in the control population with our assuys12. ApoSAA concentrations in these patients (range of peak values, 65-975 fig/ml) were correlated with TNF and with high CRP concentrations (range of peak values, 7-329 pg/ ml). ApoSAA concentrations ranged from 1 to 10 pg/ml and CRP concentrations ranged from 0.6 to 1.9 pg/nil in control populations with our assay. Statistically significant correlations between TNF levels and both apoSAA and CRP concentrations were observed for the five patients.
Molecular Metabolism, 2016
Insulin signaling plays pivotal roles in the development and metabolism of many tissues and cell ... more Insulin signaling plays pivotal roles in the development and metabolism of many tissues and cell types. A previous study demonstrated that ablation of insulin receptor (IR) with aP2-Cre markedly reduced adipose tissues mass and protected mice from obesity. However, multiple studies have demonstrated widespread non-adipocyte recombination of floxed alleles in aP2-Cre mice. These findings underscore the need to re-evaluate the role of IR in adipocyte and systemic metabolism with a more adipose tissue-specific Cre mouse line. We generated and phenotyped a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line. Here we show that the Adipoq-Cre-mediated IR KO in mice leads to lipodystrophy and metabolic dysfunction, which is in stark contrast to the previous study. In contrast to white adipocytes, absence of insulin signaling does not affect development of marrow and brown adipocytes, but instead is required for lipid accumulation particularly for the marrow adipocytes. Lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly, and impaired adipokine secretion. Our results demonstrate differential roles for insulin signaling for white, brown, and marrow adipocyte development and metabolic regulation.
... 1999 Molecular Biology of B-Cell and T-Cell Development Edited by John G. Monroe and Ellen V.... more ... 1999 Molecular Biology of B-Cell and T-Cell Development Edited by John G. Monroe and Ellen V. Rothenberg ... Deer that eat poison ivy and avoid roadways. ... separate groups in 2000 (see Chapter 7), a more detailed characterization of the pathogenesis of colitis development in ...
American Journal of Physiology Regulatory Integrative and Comparative Physiology, Oct 1, 2001
Nutrition and Health, 2007
... PEPA ATANASSOVA, MD, PhD• Department of Anatomy and Histology, Medical University, Plovdiv, B... more ... PEPA ATANASSOVA, MD, PhD• Department of Anatomy and Histology, Medical University, Plovdiv, Bulgaria ANCHA BARANOVA, PhD• Center ... BS, FRACP, MSc, PhD• Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia xix ...
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Books by Giamila Fantuzzi
Focusing on proteins that regulate inflammation and metabolism—including the cytokines and adipokines at the core of her own research—Giamila Fantuzzi examines the role body messages play in the physiology of health as well as in the pathology of various illnesses. Readers are introduced to different ways of conceptualizing biomedical research and to the advantages and pitfalls associated with identifying molecules beginning with function or structure. By bringing together areas of research usually studied separately, Fantuzzi stresses the importance of investigating the body as a whole and affirms the futility of trying to separate basic from clinical research. Drawing on firsthand interviews with researchers who made major contributions to the field, Body Messages illustrates that the paths leading to scientific discovery are rarely direct, nor are they always the only routes available.
Papers by Giamila Fantuzzi
Focusing on proteins that regulate inflammation and metabolism—including the cytokines and adipokines at the core of her own research—Giamila Fantuzzi examines the role body messages play in the physiology of health as well as in the pathology of various illnesses. Readers are introduced to different ways of conceptualizing biomedical research and to the advantages and pitfalls associated with identifying molecules beginning with function or structure. By bringing together areas of research usually studied separately, Fantuzzi stresses the importance of investigating the body as a whole and affirms the futility of trying to separate basic from clinical research. Drawing on firsthand interviews with researchers who made major contributions to the field, Body Messages illustrates that the paths leading to scientific discovery are rarely direct, nor are they always the only routes available.