Suppression of allergic reaction by lambda-carrageenan: toll-like receptor 4/MyD88-dependent and -independent modulation of immunity.
BACKGROUND
Recognition of foreign substances by innate immunity through pattern recognition receptors (PRRs) regulates acquired immunity such as allergic reaction. Because PRRs recognize heterogeneous ligands, daily food intake can potentially regulate immune allergic reaction.


OBJECTIVE
Elucidation of the effect of lambda-carrageenan on allergic reactions was aimed.


METHODS
IFN-gamma and IL-4 was measured in in vitro T cell-stimulated culture. Cytokine production from macrophages in response to lambda-carrageenan was measured as indicator for innate immunity activation. Mice were immunized with OVA in alum to induce specific IgE, and then histamine release was induced by systemic injection of OVA.


RESULTS
Activation of innate immunity by lambda-carrageenan is dependent on Toll-like receptor-4 (TLR4) and MyD88, in which induction of pro-inflammatory cytokines such as TNF-alpha and IL-6 was largely impaired in macrophages from TLR4- and MyD88-deficient mice. Footpad oedema, a model for in vivo inflammatory reactions, was significantly reduced in these mice. Similar to recent evidence showing a preference for the stimulation of Th1 via TLR/MyD88 signalling, lambda-carrageenan showed enhanced IFN-gamma and decreased IL-4 in stimulated T cell cultures. Interestingly, increased IFN-gamma production was still seen in TLR4- and MyD88-deficient splenocytes. Oral administration of lambda-carrageenan to immunized mice successfully decreased OVA-specific IgE, and lambda-carrageenan was also effective in previously immunized mice. Further, serum histamine release upon systemic challenge of OVA was significantly inhibited. Neither OVA-specific IgG1/IgG2a nor cytokine secretion from in vitro cultures were altered, suggesting the involvement of multiple PRRs as demonstrated by TLR4/MyD88-independent IFN-gamma up-regulation. The simultaneous feeding of OVA with lipopolysaccharide abrogated oral tolerance, but lambda-carrageenan was not only devoid of such an effect but was also found to promote oral tolerance in the absence of TLR4.


CONCLUSIONS
lambda-Carrageenan was suggested to be a useful dietary supplement to ameliorate allergic reactions while maintaining oral tolerance-dependent intestinal homeostasis.
Tsuji
R F
RF
Noda Institute for Scientific Research, Noda City, Japan. tsujir@Xa2.so-net.ne.jp
Hoshino
K
K
Noro
Y
Y
Tsuji
N M
NM
Kurokawa
T
T
Masuda
T
T
Akira
S
S
Nowak
B
B
D048868:Adaptor Proteins, Signal Transducing; D000284:Administration, Oral; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D002351:Carrageenan / Q000494:pharmacology*; D002478:Cells, Cultured; D029721:Drosophila Proteins; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology; D005260:Female; D006636:Histamine Release / Q000187:drug effects; D006967:Hypersensitivity / Q000517:prevention & control*; D007108:Immune Tolerance / Q000187:drug effects*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens / Q000276:immunology; D053594:Myeloid Differentiation Factor 88; D010047:Ovalbumin / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D008934:Mitogens; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D002351:Carrageenan; D010047:Ovalbumin