MECHANISM OF SPLENIC IMMUNOSUPPRESSION DURING SEPSIS - KEY ROLE OF KUPFFER CELL MEDIATORS

Studies indicate that the liver, in particular the Kupffer cells, appe ar to be key contributors in the systemic inflammatory mediator respon se associated with shock and sepsis, Although several of these agents have been implicated as mediators of depressed immunoresponsiveness ob served during sepsis, it remains unknown whether or not mediators rele ased specifically by Kupffer cells play any significant role in produc ing the cellular dysfunction in distant organs, The aim of this study, therefore, was to determine whether or not acute Kupffer cell reducti on before the onset of sepsis would protect splenic lymphocyte functio n, Kupffer cell number was reduced by prior (48 hours) treatment of mi ce with gadolinium chloride (GdCl2, 10 mg/kg of body weight, intraveno usly) or saline vehicle, Animals were then subjected to either sham-CL P (sham) or polymicrobial sepsis in the form of cecal ligation and pun cture (CLP), Plasma and splenocytes were harvested at 2 or 24 hours af ter CLP, Splenocyte cultures were exposed to 2.5 mu g concanavalin A/m L to assess their ability to release lymphokines. Cytokine (interleuki n (IL)-2, IL-6, interferon-gamma, tumor necrosis factor-alpha) concent ration in plasma or cell supernatants was assessed by bioassay. The re sults indicated that GdCl2 treated mice exhibited a marked reduction i n circulating IL-6 levels at both 2 and 24 hours after CLP, Furthermor e, the reduction of Kupffer cell number before the onset of sepsis com pletely prevented the depression of splenocyte IL-2 and interferon-gam ma release capacity, Thus mediators released by Kupffer cells during t he systemic inflammatory response to polymicrobial sepsis play a signi ficant role in producing immune dysfunction in resident splenic lympho cytes, In view of this, it appears that modulation of Kupffer cell hyp eractivity during sepsis may be a novel approach for maintaining dista nt organ host defense mechanisms.