Disruption of the murine IL-4 gene blocks Th2 cytokine responses

Abstract

Murine T-helper clones are classified into two distinct subsets (Th1 and Th2) on the basis of their patterns of lymphokine secretion. Th1 clones secrete interleukin-2 (IL-2), tumour necrosis factor-beta (TNF-beta) and interferon-gamma (IFN-gamma), whereas Th2 clones secrete IL-4, IL-5 and IL-10 (ref. 1). These subsets are reciprocally regulated by IL-4, IL-10 and IFN-gamma and differentially promote antibody or delayed-type hypersensitivity responses. To evaluate whether IL-4 is required for mounting Th2 responses, we generated IL-4-mutant mice (IL-4-/-) and assessed the cytokine secretion pattern of T cells both from naive and Nippostrongylus brasiliensis infected mice. CD4+ T cells from naive IL-4-/- mice failed to produce Th2-derived cytokines after in vitro stimulation. The levels of Th2 cytokines IL-5, IL-9 and IL-10 from CD4+ T cells obtained after nematode infection were significantly reduced. The reduced IL-5 production in IL-4-/- mice correlated with reduced helminth-induced eosinophilia, which has been shown to be dependent on IL-5 in vivo. We conclude that IL-4 is required for the generation of the Th2-derived cytokines and that immune responses dependent on these cytokines are impaired.

Immunotherapy Affects the Seasonal Increase in Specific IgE and Interleukin‐4 in Serum of Patients with Seasonal Allergic Rhinitis

“…This study included 54 adult patients (28 females and 26 males, age range, 19-55 years) with seasonal allergic rhinitis due to Japanese cedar (Cryptomeria japonica) pollens who gave informed consent for participation. All the patients were selected from our outpatients who satisfied all of the following conditions before treatment: (1) well-documented history of typical Japanese cedar pollinosis but no history of asthma and no nasal symptoms outside of the cedar pollen season; (2) positive skin test to Japanese cedar pollens; (3) positive nasal provocation test to pollens; and (4) eosinophilia in nasal smears during the cedar pollen season before treatment. The patients were divided into a medication group (12 females and 11 males) and an immunotherapy group (16 females and 15 males) based on their treatment background.…”

“…This critical role of IL-4 in isotype switching is reinforced by the observation that mice with germline disruption of the IL-4 gene fail to generate Th-2 cells in vivo and produce IgE antibodies [3]. On the other hand, interferon (IFN)-gamma inhibits the production of IgE by B lymphocytes and inhibits the development of Th-2 clones [4,5].…”

The biology of Stat4 and Stat6

“…This has been clearly demonstrated in mice de®cient for the cytokines themselves or their receptor subunits. For example, mice de®cient for IL-12 or IL-12Rb1 chain are unable to generate Th1 cells, and mice lacking IL-4 or the IL-4Ra chain are de®cient for Th2 responses (Kopf et al, 1993;Kuhn et al, 1991;Magram et al, 1996;Noben-Trauth et al, 1997;Wu et al, 1997).…”

CD45 isoform expression is associated with different susceptibilities of human naive and effector CD4+ T cells to respond to IL‐4

“…The role of cytokines for the differentiation of naive T cells to T helper (Th)1 or Th2 cells has been extensively studied in the past (reviewed in [1,2]). The development of Th2 cells has been considered to be essentially interleukin-4 (IL-4) and STAT6 dependent [3][4][5][6]. However, the development of IL-4-producing cells, although at lower frequencies, occurred in mice deficient for STAT6 [7] or deficient for IL-4R [8,9].…”