Emmanuilidis K, Weighardt H, Maier S, Gerauer K, Fleischmann T, Zheng XX, Hancock W, Holzmann B, Heidecke CD.
Critical Role of Kupffer Cell-Derived IL-10 for Host Defense in Septic Peritonitis.
J Immunol. 2001 Oct 1;167(7):3919–27.
[toggle_content title=”Abstract”]Intra-abdominal infection in patients following major visceral surgery is associated with high mortality. Using a macrophage depletion technique, we demonstrate that in murine septic peritonitis, Kupffer cells are a major source of systemic IL-10 levels. Kupffer cell-depleted mice were highly susceptible to the lethal effects of septic peritonitis and exhibited an increased bacterial load. Kupffer cell-depleted mice were protected by the administration of an IL-10-Fc fusion protein. Loss of Kupffer cell-derived IL-10 was associated with a weak increase in serum IL-12 levels, whereas TNF, IL-1, and IL-18 levels were not significantly elevated, suggesting that the loss of Kupffer cell-derived IL-10 did not result in a toxic cytokine release syndrome. Instead, loss of Kupffer cell-derived IL-10 was associated with a reduced splenocyte production of IFN- that is required for immune protection in murine septic peritonitis. Therefore, the results suggest that the protective function of IL-10 in septic peritonitis may not be restricted to the anti-inflammatory activities of IL-10. [/toggle_content] [toggle_content title=”Clodronate Liposome Parameters”] [custom_table]
Clodronate Concentration Total Lipid Concentration Lipid Composition Lipid Mole % Liposome Type Control Liposomes
5 mg/ml 23.4 mg/ml EPC/Chol 84/16 MLV none
[/custom_table] [/toggle_content] [toggle_content title=”Animals and Dosing”] [custom_table]
Animal Description Clodronate Dose Dosing Method/Site Target Phagocytes Local Dosing? Local Results
C57BL/6, female mice, 8-12 w 40 µl (diluted to 160 µl) i.v./not specified F4/80+ Kupffer cells no N/A
[/custom_table] [/toggle_content] [toggle_content title=”Notes”]
  1. Liposome prep method cited was a review, so standard clodronate liposome parameters assumed.
  2. Animals were dosed with clodronate liposomes 24 h prior to surgical procedure used to induce (peritonitis) sepsis.
  3. Some groups were splenectomized to determine the contribution of splenic macrophages.
[/toggle_content] [toggle_content title=”Results”]
  1. Peritoneal and aveolar macrophages were not reduced in number, but this was a 5X lower dose than often used in other papers (40 µl vs 200 µl).
  2. Authors report “complete” depletion of Kupffer cells along with splenic marginal macrophages and metallophilic macrophages, but not red pulp macrophages within 24 h by histology.
  3. Depletion lasted for at least 72 h.
  4. All other measurements on clodronate liposome-treated animals were either cytokine levels or IL-10 mRNA levels.
  5. The authors did not evaluate depletion in septic mice, therefore within the 12 h post-induction of sepsis (36 h post-clodronate liposome injection) before organs were harvested, would some migration of repopulating monocytes into tissues (including liver and spleen) occur?