The cytokine interleukin-4 (IL-4) is a double-edged sword: it inhibits macrophage-mediated inflammation but promotes allergy and asthma, and it promotes host control of gastrointestinal worm infections but inhibits host protection against intracellular parasites. These contrasting disease-inhibiting and disease-promoting effects of IL-4 make appropriate regulation of IL-4 responses necessary. Although several molecules suppress IL-4 responses, only one molecule induces T cells to differentiate, in vitro, into IL-4-secreting cells: IL-4 itself. Because IL-4 priming of T cell IL-4 production depends on a signaling pathway that requires activation of Stat6, it might be anticipated that Stat6-deficient mice would produce little or no IL-4; however, studies with a new technique, that directly measures IL-4 secretion in vivo, indicate that Stat6-deficient mice make normal IL-4 responses to some antigens and decreased, but still substantial IL-4 responses to other antigens. Thus, Stat6 signaling is not required for T cells to differentiate into IL-4-secreting cells in vivo. In vivo studies also indicate that IL-4 responses to some antigens decline despite continuing antigen administration; these declines are more marked in Stat6-deficient than in wild-type mice. These observations suggest four questions: 1) If Stat6-dependent IL-4 priming is not required for the in vivo development of IL-4 responses, why are IL-4 responses to some antigens considerably smaller in Stat6-deficient mice than in wild-type mice? 2) What properties account for the ability of some antigens to stimulate similar IL-4 response in wild-type and in Stat6-deficient mice, while others stimulate considerably larger IL-4 responses in wild-type mice than in Stat6-deficient mice? 3) What causes IL-4 responses to some antigens to decrease despite continuing antigenic stimulation? and 4) Why is the latter phenomenon particularly pronounced in Stat6-deficient mice? An additional observation, that the Stat6-activating cytokine IL-13 promotes in vivo type 2 cytokine responses even though it does not bind to T cells, raises a fifth question: How does Stat6 signaling of non-T cells promote IL-4 secretion? Our preliminary observations lead us to respond to these questions by hypothesizing that: 1) IL-4 production is induced, as a default response, by strong antigenic stimulation in the absence of stimuli that inhibit IL-4 production; 2) the production of antigen- antibody complexes downregulates ongoing IL-4 production by inducing the production of cytokines that inhibit IL-4 production; 3) allergens promote IL-4 responses by acting on macrophages, dendritic cells, and/or NK cells to suppress production of the cytokines that inhibit IL-4 responses; and 4) enzymatic properties of allergens contribute to their allergenicity by inhibiting macrophage, dendritic cell, and/or NK cell production of cytokines that suppress IL-4 production. Experiments to test these hypotheses will be performed with IL-4-deficient, IL-4 receptor alpha chain-deficient, Stat6-deficient, and B cell-deficient mice, and with IL-4, IL-13, IL-12, and IFN-gamma agonists and antagonists. These experiments will utilize our new assay that allows direct measurement of in vivo IL-4 production. The results of these experiments will provide a better understanding of how IL-4 responses are regulated in vivo; this understanding will enhance the ability to control disorders that are regulated by IL-4.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044971-03
Application #
6362398
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Plaut, Marshall
Project Start
1999-03-01
Project End
2003-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
3
Fiscal Year
2001
Total Cost
$183,614
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Khodoun, Marat V; Orekhova, Tatyana; Potter, Crystal et al. (2004) Basophils initiate IL-4 production during a memory T-dependent response. J Exp Med 200:857-70
Woo, Alison L; Gildea, Lucy A; Tack, Leslie M et al. (2002) In vivo evidence for interferon-gamma-mediated homeostatic mechanisms in small intestine of the NHE3 Na+/H+ exchanger knockout model of congenital diarrhea. J Biol Chem 277:49036-46
Finkelman, F D; Urban Jr, J F (2001) The other side of the coin: the protective role of the TH2 cytokines. J Allergy Clin Immunol 107:772-80
Urban Jr, J F; Noben-Trauth, N; Schopf, L et al. (2001) Cutting edge: IL-4 receptor expression by non-bone marrow-derived cells is required to expel gastrointestinal nematode parasites. J Immunol 167:6078-81
Finkelman, F D; Morris, S C; Orekhova, T et al. (2000) Stat6 regulation of in vivo IL-4 responses. J Immunol 164:2303-10
Urban Jr, J F; Schopf, L; Morris, S C et al. (2000) Stat6 signaling promotes protective immunity against Trichinella spiralis through a mast cell- and T cell-dependent mechanism. J Immunol 164:2046-52