Abstract
BackgroundHuman adipocytes may have significant functions in wound healing and the development of diabetes through production of pro-inflammatory cytokines after stimulation by gram-negative bacterial endotoxin. Diabetic foot ulcers are most often associated with staphylococcal infections. Adipocyte responses in the area of the wound may play a role in persistence and pathology. We studied the effect of staphylococcal superantigens (SAgs) on immortalized human adipocytes, alone and in the presence of bacterial endotoxin or staphylococcal α-toxin.Methodology/Principal FindingsPrimary non-diabetic and diabetic human preadipocytes were immortalized by the reverse transcriptase component of telomerase (TERT) and the E6/E7 genes of human papillomavirus. The immortal cells were demonstrated to have properties of non-immortalized pre-adipocytes and could be differentiated into mature and functional adipocytes. Differentiated adipocytes exposed to staphylococcal SAgs produced robust levels of cytokines IL-6 and IL-8, but there were no significant differences in levels between the non-diabetic and diabetic cells. Cytokine production was increased by co-incubation of adipocytes with SAgs and endotoxin together. In contrast, α-toxin alone was cytotoxic at high concentrations, but, at sub-cytotoxic doses, did not stimulate production of IL-6 and IL-8.Conclusions/SignificanceEndotoxin has been proposed to contribute to diabetes through enhanced insulin resistance after chronic exposure and stimulation of adipocytes to produce cytokines. Our data indicate staphylococcal SAgs TSST-1 and SEB alone and in combination with bacterial endotoxin also stimulate adipocytes to produce cytokines and thus may contribute to the inflammatory response found in chronic diabetic ulcers and in the systemic inflammation that is associated with the development and persistence of diabetes. The immortal human pre-adipocytes reported here will be useful for studies to understand further the mechanism by which toxins are involved in wound healing and the development and clinical manifestations of obesity and diabetes.
Highlights
Adipocytes are emerging as important participants in the development of diabetes mellitus type II (DMII) [1]
We developed diabetic and non-diabetic preadipocyte cell lines, DPAD and NPAD, which can be differentiated into adipocytes to assess responses to foreign stimuli such as endotoxin and exotoxins
With regard to bacterial infections and rodent lines, one recent study reported that S. aureus can infect mouse 3T3-L1 cells and stimulate MCP-1 and IL6 production [33], there was no attempt to determine what S. aureus factors were involved in this response
Summary
Adipocytes are emerging as important participants in the development of diabetes mellitus type II (DMII) [1]. During the expansion of adipose tissue, such as occurs in obesity, persistent inflammatory responses may occur accompanied by an upregulation of pro-inflammatory cytokines released by adipocytes. This may lead to chronic subclinical inflammation as well as insulin resistance; and contribute to the development of DMII. Endotoxin directly induces pro-inflammatory cytokine production (for example IL-6, IL-8, and TNF-a) in adipocytes via toll-like receptor 4 (TLR-4) activation, with resultant glycemia and insulinemia in experimental animals [4,5]. Human adipocytes may have significant functions in wound healing and the development of diabetes through production of pro-inflammatory cytokines after stimulation by gram-negative bacterial endotoxin. We studied the effect of staphylococcal superantigens (SAgs) on immortalized human adipocytes, alone and in the presence of bacterial endotoxin or staphylococcal a-toxin
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