ABSTRACT
Gene mutations in the virulence regulator CovR/S of group A Streptococcus play a substantial role in the pathogenesis of streptococcal toxic shock syndrome. We screened 25 group B Streptococcus (GBS) isolates obtained from patients with streptococcal toxic shock syndrome and found only 1 GBS clone harboring this kind of mutation.
Subject(s)
Bacterial Proteins/genetics , Gene Expression Regulation, Bacterial , Mutation , Repressor Proteins/genetics , Shock, Septic/microbiology , Streptococcal Infections/microbiology , Streptococcus agalactiae/pathogenicity , Virulence Factors/genetics , Adult , Aged , Aged, 80 and over , Bacterial Proteins/metabolism , Female , Humans , Infant, Newborn , Male , Middle Aged , Multilocus Sequence Typing , Repressor Proteins/metabolism , Serotyping , Shock, Septic/mortality , Shock, Septic/pathology , Streptococcal Infections/mortality , Streptococcal Infections/pathology , Streptococcus agalactiae/classification , Streptococcus agalactiae/genetics , Survival Analysis , Virulence , Virulence Factors/metabolismABSTRACT
Upon obesity, adipose tissue is excessively expanded and characterized by pathologic processes like hypoxia, fibrosis, and inflammation. Death ligands belonging to the TNF superfamily such as TNF-α are important contributors to these derangements and exert a pronounced influence on the metabolic and cellular homeostasis of adipose tissue. Here, we sought to identify the effect of the death ligand TNF-related apoptosis-inducing ligand (TRAIL) on the adipose tissue precursor cell pool and therefore investigated its influence on preadipocyte proliferation. Treatment of human preadipocytes with TRAIL resulted in a time- and dose-dependent increase in proliferation (EC50 3.4 ng/ml) comparable to IGF-1. Although no apoptosis was observed, TRAIL triggered a rapid cleavage of caspase-8 and -3. Neither inhibition of caspase activity by zVAD.fmk (20 µM) nor ablation of caspase-8 expression by lentivirus-delivered small hairpin RNA (shRNA) abolished the proliferative response. TRAIL triggered a delayed and sustained activation of ERK1/2, leaving Akt, p38, JNK, and NF-κB unaffected. Importantly, inhibition of ERK1/2 activation by PD0325901 (300 nM) or AZD6244 (5 or 10 µM) completely abolished the proliferative response. We thus reveal a hitherto unknown function of TRAIL in regulating adipose tissue homeostasis by promoting the proliferation of tissue-resident precursor cells.