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Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.

Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K - J. Exp. Med. (2002)

Bottom Line: Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming.The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells.In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.

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Related in: MedlinePlus

Differential IL-12 production with high and low dose LPS. (A) Serum IL-12 (p70) levels on day 2 of priming with inhaled OVA containing either high (100 μg) or low (0.1 μg) levels of LPS. (B) IL-12 (p70) production from WT or TLR4d BMDCs after stimulation with 100 μg/ml OVA with low dose LPS, 100 ng/ml TNF-α, or high dose (50 ng/ml) LPS for 12 h. ND, not detectable.
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fig5: Differential IL-12 production with high and low dose LPS. (A) Serum IL-12 (p70) levels on day 2 of priming with inhaled OVA containing either high (100 μg) or low (0.1 μg) levels of LPS. (B) IL-12 (p70) production from WT or TLR4d BMDCs after stimulation with 100 μg/ml OVA with low dose LPS, 100 ng/ml TNF-α, or high dose (50 ng/ml) LPS for 12 h. ND, not detectable.

Mentions: LPS is known to induce both cell surface DC maturation and the production of TNF-α, IL-1, and IL-12 (3). As IL-12 is a potent Th1 skewing cytokine, we hypothesized that differences in IL-12 production following high versus low dose LPS inhalation with OVA might explain the induction of Th1 versus Th2 responses, respectively. To test this, serum IL-12 levels were analyzed. In contrast to mice immunized with low dose LPS OVA, WT mice immunized with high dose LPS OVA had significantly higher levels of serum IL-12 (Fig. 5 A). In vitro evaluation of WT BMDC confirmed that only high dose LPS was capable of inducing IL-12 production, whereas OVA (containing low dose LPS) did not (Fig. 5 B). These data are consistent with the differential inflammatory response observed in vivo (Th1 vs. Th2) and implicate an LPS threshold requirement for IL-12 secretion. Interestingly, TNF-α, a cytokine capable of inducing DC maturation and Th2 sensitization, was unable to induce IL-12 in WT BMDCs. This is consistent with our observations that TNF-α administration during priming was capable of rescuing Th2 responses in TLR4d mice without the induction of Th1 immunity (Fig. 4 A). As expected, no IL-12 was detected from TLR4d serum or BMDCs stimulated with OVA, TNF-α, or LPS.


Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.

Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K - J. Exp. Med. (2002)

Differential IL-12 production with high and low dose LPS. (A) Serum IL-12 (p70) levels on day 2 of priming with inhaled OVA containing either high (100 μg) or low (0.1 μg) levels of LPS. (B) IL-12 (p70) production from WT or TLR4d BMDCs after stimulation with 100 μg/ml OVA with low dose LPS, 100 ng/ml TNF-α, or high dose (50 ng/ml) LPS for 12 h. ND, not detectable.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196061&req=5

fig5: Differential IL-12 production with high and low dose LPS. (A) Serum IL-12 (p70) levels on day 2 of priming with inhaled OVA containing either high (100 μg) or low (0.1 μg) levels of LPS. (B) IL-12 (p70) production from WT or TLR4d BMDCs after stimulation with 100 μg/ml OVA with low dose LPS, 100 ng/ml TNF-α, or high dose (50 ng/ml) LPS for 12 h. ND, not detectable.
Mentions: LPS is known to induce both cell surface DC maturation and the production of TNF-α, IL-1, and IL-12 (3). As IL-12 is a potent Th1 skewing cytokine, we hypothesized that differences in IL-12 production following high versus low dose LPS inhalation with OVA might explain the induction of Th1 versus Th2 responses, respectively. To test this, serum IL-12 levels were analyzed. In contrast to mice immunized with low dose LPS OVA, WT mice immunized with high dose LPS OVA had significantly higher levels of serum IL-12 (Fig. 5 A). In vitro evaluation of WT BMDC confirmed that only high dose LPS was capable of inducing IL-12 production, whereas OVA (containing low dose LPS) did not (Fig. 5 B). These data are consistent with the differential inflammatory response observed in vivo (Th1 vs. Th2) and implicate an LPS threshold requirement for IL-12 secretion. Interestingly, TNF-α, a cytokine capable of inducing DC maturation and Th2 sensitization, was unable to induce IL-12 in WT BMDCs. This is consistent with our observations that TNF-α administration during priming was capable of rescuing Th2 responses in TLR4d mice without the induction of Th1 immunity (Fig. 4 A). As expected, no IL-12 was detected from TLR4d serum or BMDCs stimulated with OVA, TNF-α, or LPS.

Bottom Line: Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming.The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells.In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.

Show MeSH
Related in: MedlinePlus