Restoration of Natural IgM Production from Liver B Cells by Exogenous IL-18 Improves the Survival of Burn-Injured Mice Infected with Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is the most common bacterium of postburn infection. In the present study we investigated the immune mechanism of susceptibility to this type of postburn infection and also examined the efficacy of IL-18 treatment. C57BL/6 mice were challenged with P. aeruginosa on day 7 after burn injury. Although the burn-injured mice showed a poor survival rate after bacterial challenge, they retained their IFN-γ production. The burned mice showed lower serum IgM levels and a poor IgM response following P. aeruginosa challenge in comparison with the sham mice, whereas IL-18 treatment after burn injury (alternate day injections for 1 wk) greatly improved the serum IgM levels, which are P. aeruginosa-independent natural IgM before bacterial challenge, thereby increasing the survival rate after the challenge. IL-18 treatment also induced specific IgM to P. aeruginosa in the sera 5 days after bacterial challenge in the burned mice. Interestingly, CD43+CD5−CD23−B220dim cells, namely B-1b cells, increased in the liver after the IL-18 treatment and were found to actively produce IgM in vitro without any additional stimulation. Furthermore, the IL-18 treatment up-regulated the neutrophil count and the C3a levels in the blood as a result of the increased IgM level, which may thus play a critical role in the opsonization and elimination of any invading bacteria. IL-18 treatment for the burned mice and their resultant natural IgM production were thus found to strengthen the host defense against P. aeruginosa infection.

Enhancement of Neutrophil Function by Interleukin-18 Therapy Protects Burn-Injured Mice from Methicillin-Resistant Staphylococcus aureus

“…However, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, not E. coli, are the most common bacteria in postburn infections (11,34). In contrast to the response to E. coli infection, burn-injured mice retain IFN-␥ production against P. aeruginosa infection (23). Nevertheless, they also show poor survival because natural IgM production, which is crucial for preventing P. aeruginosa infection, is suppressed in the mice after burn injury.…”

“…NOD-SCID (nonobese diabetic, severe combined immunodeficiency) mice (8 weeks old, 20 g; Charles River, Inc., Yokohama, Japan) were also used. As we previously described (1,22,23), mice were anesthetized using an intraperitoneal (i.p.) injection with pentobarbital (1 mg/mouse; Abbott Laboratories, North Chicago, IL).…”

“…Nevertheless, they also show poor survival because natural IgM production, which is crucial for preventing P. aeruginosa infection, is suppressed in the mice after burn injury. Interestingly, IL-18 treatment following burn injury also restores the natural IgM production in the liver, thereby improving mouse survival from postburn P. aeruginosa infection (23). IL-18 treatment might thus effectively augment both IFN-␥-mediated cellular and IgM-mediated humoral immunities.…”

A revival for immunoglobulin therapy in septic shock?

“…Natural IgM antibodies are constitutively secreted by B1 cells. Several elegant animal models have demonstrated the protective role of natural IgM against numerous viral, bacterial, and parasitic infections (Influenza, Pseudomonas aeruginosa, Plasmodium falciparum) and a worse outcome of patients with IgM deficiency [5][6][7]. IgM has an important role in the classical pathway of complement activation when complexed with antigens and its pentameric structure favors agglutination of the invading organism and its neutralization.…”

Cimetidine enhances delayed-type hypersensitivity responses and serum interleukin (IL)-2, -10, -12, and IL-17 levels after burn injury in an animal model

“…Some investigations have indicated that burn-induced immunosuppression could be overcome through administration of select cytokines (Kinoshita et al, 2006), hormones (Kovacs et al, 2004), antioxidants (Cetinkalee et al, 1999), CpG oligonucleotides (Yabuki et al, 2010), and/or immunomodulating drugs like indomethacin (Choudhry et al, 2002) and cimetidine (Gharegozloo et al, 2004), as well as by surgical excision of the burn wound (Kovacs et al, 2004). We recently demonstrated that cimetidine restores burn-induced suppression of delayed-type hypersensitivity (DTH) responses at 10 days post-thermal trauma (Jafarzadeh et al, 2010).…”