title: Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications.
abstract: Diabetes mellitus type 1 (DMT1) is an autoimmune disease characterized by the destruction of insulin-producing cells in the pancreas. Diabetic patients are more susceptible to recurrent and uncontrolled infections, with worse prognoses than in healthy individuals. Macrophages (MΦs) derived from DMT1 individuals have compromised mounting of inflammatory and immune responses. The mechanisms responsible for these alterations remain unknown. It has been shown that the presence of extra- and intracellular heat shock proteins (hsp) positively modulates immune cell function. Using naive MΦs derived from non-obese diabetic (NOD) mice, a well-established mouse model for DMT1, we demonstrate that heat shock (HS) as well as treatment with geldanamycin (GA), significantly improves diabetic MΦ activation, resulting in increased phagocytosis and killing of bacteria. Induction of HS did not affect the aberrant NOD-MΦ cytokine profile, which is characterized by elevated IL-10 levels and normal tumor necrosis factor alpha. Our observations were consistent at pre-diabetic (normal random blood glucose) and diabetic (random blood glucose greater than 250 mg/dl) stages, suggesting that HS and GA treatment may compensate for intrinsic genetic alterations present in diabetic cells regardless of the stage of the disease. The mechanisms associated to this phenomenon are unknown, but they may likely be associated with the induction of hsp expression, a common factor between HS and GA treatment. Our results may open a new field for non-classical function of hsp and indicate that hsp expression may be used as a part of therapeutic approaches for the treatment of complications associated with DMT1 as well as other autoimmune diseases.
authors.affiliation: Department of Surgery, University of California San Diego, La Jolla, CA, 92093-0739, USA. vvega@ucsd.edu
authors.forename: Virginia Loreto
authors.initials: VL
authors.lastname: Vega
authors.forename: Wisler
authors.initials: W
authors.lastname: Charles
authors.forename: Laura E
authors.initials: LE
authors.lastname: Crotty Alexander
authors.forename: Laura E Crotty
authors.initials: LE
authors.lastname: Alexander
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000502:physiology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010587:Phagocytosis / Q000502:physiology*
chemical_list: D016227:Benzoquinones; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C001277:geldanamycin