Differences in expression, affinity, and function of soluble (s)IL-4Ralpha and sIL-13Ralpha2 suggest opposite effects on allergic responses.
IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4Ralpha and sIL-13Ralpha2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4Ralpha complexes rapidly dissociate, releasing active IL-4, whereas sIL-13Ralpha2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13Ralpha2, IL-4, or sIL-4Ralpha. Approximately 25% of sIL-13Ralpha2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13Ralpha2 in serum increase considerably during a Th2 response. sIL-13Ralpha2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4Ralpha-dependent while the effect of IL-13 is partially IL-4Ralpha-independent. Inhalation of an IL-13/sIL-13Ralpha2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4Ralpha predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13Ralpha2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.
Khodoun
Marat
M
Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
Lewis
Christina C
CC
Lewis
Christina
C
Yang
Jun-Qi
JQ
Orekov
Tatyana
T
Potter
Crystal
C
Wynn
Thomas
T
Mentink-Kane
Margaret
M
Hershey
Gurjit K Khurana
GK
Wills-Karp
Marsha
M
Finkelman
Fred D
FD
D000581:Amidohydrolases; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006207:Half-Life; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology; D012995:Solubility; D053662:Interleukin-4 Receptor alpha Subunit
D000581:Amidohydrolases; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D015847:Interleukin-4; D046912:Multiprotein Complexes; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C105948:Pira1 protein, mouse; C022314:pantetheinase