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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

TLR4d mice sensitized intraperitoneally with the adjuvant aluminum hydroxide are capable of generating Th2 responses to OVA. (A) WT and TLR4d were primed either intranasally with OVA or intraperitoneally with OVA in alum and BAL was evaluated on day 21 after standard intranasal challenge. Stacked bars of cell differential are shown. Total BAL cell number is represented by height of stacked bars and standard error is based on total BAL number. *, P < 0.005 (intranasally primed TLR4d vs. WT mice). Mice immunized intraperitoneally with alum alone did not respond. (B) Cytokine production in pg/ml from DLN of intranasally or intraperitoneally primed WT (solid bars) or TLR4d (open bars) mice. ND, not detectable. IFN-γ was not detectable from cultures of WT or TLR4d mice primed intranasally or intraperitoneally with OVA containing a low dose of LPS. One representative experiment of two is shown.
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fig3: TLR4d mice sensitized intraperitoneally with the adjuvant aluminum hydroxide are capable of generating Th2 responses to OVA. (A) WT and TLR4d were primed either intranasally with OVA or intraperitoneally with OVA in alum and BAL was evaluated on day 21 after standard intranasal challenge. Stacked bars of cell differential are shown. Total BAL cell number is represented by height of stacked bars and standard error is based on total BAL number. *, P < 0.005 (intranasally primed TLR4d vs. WT mice). Mice immunized intraperitoneally with alum alone did not respond. (B) Cytokine production in pg/ml from DLN of intranasally or intraperitoneally primed WT (solid bars) or TLR4d (open bars) mice. ND, not detectable. IFN-γ was not detectable from cultures of WT or TLR4d mice primed intranasally or intraperitoneally with OVA containing a low dose of LPS. One representative experiment of two is shown.

Mentions: Mice were anesthetized with methoxyflurane (Metofane) and then sensitized intranasally with 100 μg OVA (Grade V; Sigma-Aldrich) in 50 μl PBS on days 0, 1, and 2 as previously described (8). For Fig. 3, we sensitized WT or TLR4d mice intraperitoneally with 100 μg OVA in 2 mg aluminum hydroxide (Pierce Chemical Co.) in a total volume of 0.25 ml.


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)

TLR4d mice sensitized intraperitoneally with the adjuvant aluminum hydroxide are capable of generating Th2 responses to OVA. (A) WT and TLR4d were primed either intranasally with OVA or intraperitoneally with OVA in alum and BAL was evaluated on day 21 after standard intranasal challenge. Stacked bars of cell differential are shown. Total BAL cell number is represented by height of stacked bars and standard error is based on total BAL number. *, P < 0.005 (intranasally primed TLR4d vs. WT mice). Mice immunized intraperitoneally with alum alone did not respond. (B) Cytokine production in pg/ml from DLN of intranasally or intraperitoneally primed WT (solid bars) or TLR4d (open bars) mice. ND, not detectable. IFN-γ was not detectable from cultures of WT or TLR4d mice primed intranasally or intraperitoneally with OVA containing a low dose of LPS. One representative experiment of two is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196061&req=5

fig3: TLR4d mice sensitized intraperitoneally with the adjuvant aluminum hydroxide are capable of generating Th2 responses to OVA. (A) WT and TLR4d were primed either intranasally with OVA or intraperitoneally with OVA in alum and BAL was evaluated on day 21 after standard intranasal challenge. Stacked bars of cell differential are shown. Total BAL cell number is represented by height of stacked bars and standard error is based on total BAL number. *, P < 0.005 (intranasally primed TLR4d vs. WT mice). Mice immunized intraperitoneally with alum alone did not respond. (B) Cytokine production in pg/ml from DLN of intranasally or intraperitoneally primed WT (solid bars) or TLR4d (open bars) mice. ND, not detectable. IFN-γ was not detectable from cultures of WT or TLR4d mice primed intranasally or intraperitoneally with OVA containing a low dose of LPS. One representative experiment of two is shown.
Mentions: Mice were anesthetized with methoxyflurane (Metofane) and then sensitized intranasally with 100 μg OVA (Grade V; Sigma-Aldrich) in 50 μl PBS on days 0, 1, and 2 as previously described (8). For Fig. 3, we sensitized WT or TLR4d mice intraperitoneally with 100 μg OVA in 2 mg aluminum hydroxide (Pierce Chemical Co.) in a total volume of 0.25 ml.

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