title: Cytokine profiling in patients with VCP-associated disease.
abstract: Valosin containing protein (VCP) disease (also known as Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia [IBMPFD] syndrome) is caused by mutations in the gene encoding VCP classically affecting the muscle, bone and brain. Although the genetic cause has been identified, details regarding the pathogenesis of IBMPFD have not been fully determined. Muscle wasting observed in VCP disease is suggestive of cytokine imbalance. We hypothesized that dysfunctional protein homeostasis caused by VCP mutations leads to cytokine imbalances thereby contributing to the muscle wasting phenotype. Circulating levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF a) and epidermal growth factor (EGF) were measured in plasma of patients with VCP disease or controls. TNF a and EGF were significantly altered in VCP disease as compared to control. TNF a was up-regulated, consistent with a cachexia phenotype and EGF levels were increased. No significant differences were observed in IL-4 and IL-6. Cytokine imbalances may be associated with VCP disease and may play a contributory role in VCP myopathy. Further understanding of how VCP dysfunction leads to aberrant protein homeostasis and subsequent cytokine imbalances may also aid in the understanding of other proteinopathies and in the development of novel treatments.
authors.affiliation: Division of Genetics and Metabolism, Department of Pediatrics, University of California, Irvine, California, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Dec
authors.forename: Prachi
authors.initials: P
authors.lastname: Rana
authors.forename: Veeral
authors.initials: V
authors.lastname: Katheria
authors.forename: Rachel
authors.initials: R
authors.lastname: Dec
authors.forename: Manaswitha
authors.initials: M
authors.lastname: Khare
authors.forename: Angèle
authors.initials: A
authors.lastname: Nalbandian
authors.forename: Szu-Yun
authors.initials: SY
authors.lastname: Leu
authors.forename: Shlomit
authors.initials: S
authors.lastname: Radom-Aizik
authors.forename: Katrina
authors.initials: K
authors.lastname: Llewellyn
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
authors.forename: Frank
authors.initials: F
authors.lastname: Zaldivar
authors.forename: Virginia
authors.initials: V
authors.lastname: Kimonis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D016207:Cytokines / Q000097:blood*; D004815:Epidermal Growth Factor / Q000097:blood*; D057180:Frontotemporal Dementia / Q000097:blood* / Q000209:etiology / Q000235:genetics; D006801:Humans; D015847:Interleukin-4 / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood*; D024510:Muscle Development / Q000235:genetics / Q000502:physiology; D009133:Muscular Atrophy / Q000097:blood / Q000209:etiology / Q000235:genetics; D049288:Muscular Dystrophies, Limb-Girdle / Q000097:blood* / Q000209:etiology / Q000235:genetics; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000097:blood* / Q000209:etiology / Q000235:genetics; D010001:Osteitis Deformans / Q000097:blood* / Q000209:etiology / Q000235:genetics; D015398:Signal Transduction; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; C508598:IL4 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D004815:Epidermal Growth Factor; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: IBMPFD; VCP; cytokines