title: Local TH1 and TH2 responses to parasitic infection in the intestine: regulation by IFN-gamma and IL-4.
abstract: Control of parasitic infections is dependent on the production of cytokines that activate mechanisms which limit invasion, reproduction or survival of the parasite. In contrast, conditions that induce inappropriate cytokine responses facilitate the spread of infection and ultimately exacerbate the level of disease. Measurement of local cytokine responses to different gastrointestinal parasites, such as the intracellular protozoan, Cryptosporidium parvum, and luminal dwelling nematodes like Nippostrongylus brasiliensis and Heligmosomoides polygyrus, reveal stereotype response patterns. In general, intracellular parasites stimulate type 1 responses where IFN-gamma is the predominant immune activator, while extracellular parasites stimulate type 2 responses where IL-4 plays a prominent role in elevating humoral immune mechanisms. Cytokines alter cellular function and the milieu of the intestinal lumen to affect the outcome of an infection. The importance of a particular response during the course of an infection can be studied by selective enhancement with an excess of exogenous recombinant cytokine or cytokine antagonists. For example, exogenous IL-12 enhances resistance to C.parvum, but suppresses the normally rapid cure of an infection with N. brasiliensis. Both mechanisms are dependent on expression of IFN-gamma. At the molecular level, exogenous IL-12 stimulates IFN-gamma production which elevates a protective type 1 response to C. parvum but converts the normally anti-worm type 2 response to a type 1 response that inappropriately regulates the infection. Alternatively, excess IL-4 plays a prominent role in modulating effector elements that change intestinal physiology to create a hostile environment for worm parasites. Exogenous IL-4 can cure chronic worm infection, while IL-4 antagonists interfere with protective responses to infection. These observations provide a paradigm for analysis of stereotype responses to different gastrointestinal parasites, and demonstrate how cytokine-induced immune system-dependent and independent effector mechanisms can limit parasitic infection, while inappropriate cytokine responses can exacerbate the state of disease.
authors.affiliation: Immunology and Disease Resistance Laboratory, Livestock and Poultry Sciences Institute, Beltsville, MD 20705, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Urban
authors.forename: R
authors.initials: R
authors.lastname: Fayer
authors.forename: C
authors.initials: C
authors.lastname: Sullivan
authors.forename: J
authors.initials: J
authors.lastname: Goldhill
authors.forename: T
authors.initials: T
authors.lastname: Shea-Donohue
authors.forename: K
authors.initials: K
authors.lastname: Madden
authors.forename: S C
authors.initials: SC
authors.lastname: Morris
authors.forename: I
authors.initials: I
authors.lastname: Katona
authors.forename: W
authors.initials: W
authors.lastname: Gause
authors.forename: M
authors.initials: M
authors.lastname: Ruff
authors.forename: L S
authors.initials: LS
authors.lastname: Mansfield
authors.forename: F D
authors.initials: FD
authors.lastname: Finkelman
mesh_terms: D000818:Animals; D003457:Cryptosporidiosis / Q000276:immunology*; D016785:Cryptosporidium parvum / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D016513:Mice, SCID; D009351:Nematospiroides dubius / Q000276:immunology; D009559:Nippostrongylus / Q000276:immunology; D017206:Strongylida Infections / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology*
chemical_list: D015847:Interleukin-4; D007371:Interferon-gamma