RESUMO
Endotoxin tolerance is a phenomenon characterized by a reduced capacity of monocytes and macrophages to respond to repeated stimulation with lipopolysaccharide (LPS) which has been suggested to represent a way of controlling the intensity and duration of innate immune response. During endotoxin tolerance, monocytes undergo functional re-programming primarily by epigenetic regulation. Recently, micro-RNA (miR)-146a has been demonstrated to be the major player of the negative regulation of the pro-inflammatory response, affecting TNF-α production. In this study, we have employed CyP, a cyanobacterial LPS antagonist acting on TLR4-MD2 complex, for priming human monocytes and evaluating their response to a subsequent challenge with E. coli LPS. Results show that CyP is able to induce cross-tolerance to E. coli LPS by inhibiting TNF-α production. The mechanism of action is mediated by a specific induction of miR-146a and reduction of IRAK1 and TRAF6 expressions in human monocytes by CyP priming. Up-regulation of miR-146a by CyP alone, affects subsequent cell response in term of TNF-α production even when monocytes are incubated with other TLR ligands, as lipoteichoic acid (LTA), thus confirming miR-146a as a critical player mediating TNF-α regulation during cross-tolerance with CyP.
Assuntos
Cianobactérias/metabolismo , Endotoxinas/toxicidade , Tolerância Imunológica , Lipopolissacarídeos/toxicidade , MicroRNAs/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Tolerância Imunológica/efeitos dos fármacos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Lipopolissacarídeos/farmacologia , MicroRNAs/genética , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Células THP-1 , Fator 6 Associado a Receptor de TNF/metabolismo , Ácidos Teicoicos/farmacologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
BACKGROUND: The present work proposes to explore a phenomenon well known in the world of blood donation, but little explored by literature: multi-affiliations. By that term, in this paper we mean blood donors' engagement in multiple associations of various natures (donation, recreation, sports, etc.) simultaneously. The first objective proposes to explore the phenomenon of multi-affiliations in descriptive terms; the second is to look into the differences-in terms of motivations, family-work-volunteerism reconciliation, life satisfaction, and membership satisfaction-between those who "only" carry out blood donation activity and those who instead participate in multiple associative realities concurrently. METHOD: Participating in the research were 2674 donors from the Italian Association of Blood Donors (AVIS) (age range 18-65; 66.6% male) to which a self-report questionnaire was administered in the waiting rooms of numerous blood donation centers. RESULTS: Regarding the first objective, it emerged that only 35.9% of the participants "only" donate blood, while a good 64.1% is engaged also in other associations. Regarding the second objective, statistically significant differences emerge regarding many of the variables considered: social, values, ego-protection, and career motivation; capacity to reconcile family-volunteering and work-volunteering; life satisfaction; and membership satisfaction. CONCLUSIONS: The study offers precious information to the agencies that handle recruiting and retaining of donors. The agencies in fact can take away information on how to improve the multi-affiliations of their donors, an aspect that can facilitate their long-term retention.