Dual roles for LPS depending on concentration

Abstract

Epidemiologic studies suggest that exposure to LPS or other microbial products influences the development and severity of asthma. Previous studies have primarily shown that Toll-like receptors (TLRs) are required for adaptive TH1 responses, but the role of TLRs in TH2 events has been unclear. In the current study, the investigators examined the effect of LPS on the induction of TH1 and TH2 responses in the lungs. The investigators demonstrated that the ability of intranasal ovalbumin (OVA) to induce experimental asthma (in the absence of alum or other known adjuvants) was dependent on trace levels of endotoxin present as a contaminant in the OVA preparations used. In particular, when they depleted the traces of contaminating LPS, OVA lost its ability to induce TH2 responses. When they sensitized mice with OVA spiked with low concentrations and high concentrations of LPS, TH2 and TH1 responses, respectively, were induced. TLR4 signaling was required for TH2 priming to inhaled antigens, as shown through use of TLR4-deficient animals (C.C3H-Tlr4Lps-D). The role of TLR4 was specific for LPS-modulated sensitization to OVA, inasmuch as these TLR4-deficient mice were still capable of mounting TH2 responses to OVA when the classic adjuvant, alum, was used. Notably, in the absence of TLR4 signaling, the administration of TNF-α was able to restore OVA-induced pulmonary inflammation. Finally, the investigators demonstrated that the mechanism by which endotoxin induced TH2 responses was related to dendritic cell maturation and migration to draining lymph nodes. Furthermore, in comparison with exposure to low doses of LPS, exposure to high doses of LPS induced dendritic cells to produce IL-12. These studies suggest that the level of LPS exposure might determine the type of pulmonary inflammatory response and provide a potential mechanistic explanation of epidemiologic data on endotoxin exposure's affecting the development of asthma.(Eisenbarth et al. J Exp Med 2002;196:1645-51) Epidemiologic studies suggest that exposure to LPS or other microbial products influences the development and severity of asthma. Previous studies have primarily shown that Toll-like receptors (TLRs) are required for adaptive TH1 responses, but the role of TLRs in TH2 events has been unclear. In the current study, the investigators examined the effect of LPS on the induction of TH1 and TH2 responses in the lungs. The investigators demonstrated that the ability of intranasal ovalbumin (OVA) to induce experimental asthma (in the absence of alum or other known adjuvants) was dependent on trace levels of endotoxin present as a contaminant in the OVA preparations used. In particular, when they depleted the traces of contaminating LPS, OVA lost its ability to induce TH2 responses. When they sensitized mice with OVA spiked with low concentrations and high concentrations of LPS, TH2 and TH1 responses, respectively, were induced. TLR4 signaling was required for TH2 priming to inhaled antigens, as shown through use of TLR4-deficient animals (C.C3H-Tlr4Lps-D). The role of TLR4 was specific for LPS-modulated sensitization to OVA, inasmuch as these TLR4-deficient mice were still capable of mounting TH2 responses to OVA when the classic adjuvant, alum, was used. Notably, in the absence of TLR4 signaling, the administration of TNF-α was able to restore OVA-induced pulmonary inflammation. Finally, the investigators demonstrated that the mechanism by which endotoxin induced TH2 responses was related to dendritic cell maturation and migration to draining lymph nodes. Furthermore, in comparison with exposure to low doses of LPS, exposure to high doses of LPS induced dendritic cells to produce IL-12. These studies suggest that the level of LPS exposure might determine the type of pulmonary inflammatory response and provide a potential mechanistic explanation of epidemiologic data on endotoxin exposure's affecting the development of asthma. (Eisenbarth et al. J Exp Med 2002;196:1645-51)