IntroductionCytokines of the interleukin (IL)-1 family are major proinflammatory and immunoregulatory mediators that act through receptors of the Toll-like/IL-1-receptor (TLR/IL-1R) superfamily. Due to homologous intracellular Toll/interleukin-1 receptor (TIR) domains, IL-1 family members and TLR-ligands activate very similar signaling pathways leading to NF-B-and MAPKactivation. 1 IL-1␣ and IL-1␤, the prototypic family members, are generated in response to exogenous and endogenous danger signals and act as chief inflammatory mediators in many inflammatory conditions. 2 Recent studies indicate that IL-1 may also participate in inflammatory pathologies and auto-immune diseases involving Th17-type T-helper cells. [3][4][5] By contrast, IL-18 is best known for its role in Th1-type immune responses because it strongly amplifies IFN-␥ production in natural killer (NK) cells and Th1 cells in synergy with However, several lines of evidence mainly derived from mouse models indicate that IL-18 can also play a role in allergic diseases and defense against helminths. 6,7 For example, in the absence of IFN-␥ signaling, IL-18 increases immunoglobulin E (IgE) levels and promotes a Th2-type pathology. 8 It has been suggested that this is due to the antigen-independent action of IL-18 on cells of the "innate allergic response," basophils and mast cells. 7 Bone marrow-derived c-Kit Ϫ /Fc⑀RI ϩ mouse "basophil-like" cells express IL-18 receptors (IL-18R), and IL-18 induces IL-4 and IL-13 expression in an antigen-independent manner as efficiently as In the human system, IL-18 primes basophilic KU812 cells for enhanced leukotriene C 4 (LTC 4 ) production. 9 Furthermore, a recent screen of novel CD antigens revealed that blood basophils express IL-18R and IL-18R-accessory protein (IL-18Rap), 10 indicating that IL-18 may also act on human basophils.A soluble form of an IL-1R family member ST2 (sST2; also called T1) has been cloned many years ago. sST2 is formed by many cells and increased sST2 levels are found in inflammatory conditions, including allergic asthma. [11][12][13] The expression of transmembrane ST2-receptor (ST2L), however, is largely restricted to cells of hematopoietic origin. ST2L is expressed by mouse bone marrow-derived mast cells (BMMCs) and is a stable marker of mouse, but not human, Th2-lymphocytes. [14][15][16][17] In the absence of a known ligand, the biologic roles of ST2 have been extensively studied in several mouse models using ST2-antibodies, sST2-constructs, and ST2-KO-mice. 14,18 Although the interpretations were sometimes conflicting, most studies indicate an important contribution of ST2 in Th2-type immune responses and allergic inflammation. The biology of ST2 is further complicated by a possible direct antiinflammatory action of sST2, and by the fact that the TIR domain of ST2L appears to be a negative regulator of 20 Research on ST2 strongly gained momentum by the recent discovery of its ligand, the novel IL-1 family member IL-33. 21 Like IL-1␣, the human IL-33 precursor (proIL-33) is a nuclear pr...

SUP35 is an omnipotent suppressor gene of Saccharomyces cerevisiae coding for a protein consisting of a C-terminal part similar to the elongation factor EF-1 alpha and a unique N-terminal sequence of 253 amino acids. Twelve truncated versions of the SUP35 gene were generated by the deletion of fragments internal to the coding sequence. Functional studies of these deletion mutants showed that: (i) only the EF-1 alpha-like C-terminal part of the Sup35 protein is essential for the cell viability; (ii) overexpression of either the N-terminal part of the Sup35 protein or the full-length Sup35 protein decreases translational fidelity, resulting in omnipotent suppression and reduced growth of [psi+] strains; (iii) expression of the C-terminal part of the Sup35 protein generates an antisuppressor phenotype; and (iv) both the N- or C-terminal segments of the Sup35 protein can bind to 80S ribosomes. Thus, the data obtained define two domains within the Sup35 protein which are responsible for different functions.

Histamine, leukotriene C4, IL-4, and IL-13 are major mediators of allergy and asthma. They are all formed by basophils and are released in particularly large quantities after stimulation with IL-3. Here we show that supernatants of activated mast cells or IL-3 qualitatively change the makeup of granules of human basophils by inducing de novo synthesis of granzyme B (GzmB), without induction of other granule proteins expressed by cytotoxic lymphocytes (granzyme A, perforin). This bioactivity of IL-3 is not shared by other cytokines known to regulate the function of basophils or lymphocytes. The IL-3 effect is restricted to basophil granulocytes as no constitutive or inducible expression of GzmB is detected in eosinophils or neutrophils. GzmB is induced within 6 to 24 hours, sorted into the granule compartment, and released by exocytosis upon IgE-dependent and -independent activation. In vitro, there is a close parallelism between GzmB, IL-13, and leukotriene C4 production. In vivo, granzyme B, but not the lymphoid granule marker granzyme A, is released 18 hours after allergen challenge of asthmatic patients in strong correlation with interleukin-13. Our study demonstrates an unexpected plasticity of the granule composition of mature basophils and suggests a role of granzyme B as a novel mediator of allergic diseases.