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Cytokines are inflammatory mediators important in responding to pathogens and other foreign challenges. Interleukin-4 (IL-4) and IL-13 are two cytokines produced by T helper type 2 cells, mast cells, and basophils. In addition to their physiological roles, these cytokines are also implicated in pathological conditions such as asthma and allergy. IL-4 can stimulate two receptors, type I and type II, whereas IL-13 signaling is mediated only by the type II receptor (see the STKE Connections Maps). These cytokines activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascades, which may contribute to allergic responses. In addition, stimulation of the phosphatidylinositol 3-kinase (PI3K) pathway through recruitment of members of the insulin receptor substrate family may contribute to survival and proliferation.
The discovery of lymphokines stemmed from their ability to promote T-lymphocyte proliferation in vitro. Even after 20 years of intensive investigation, crucial aspects remain to be clarified about the role of specific lymphokines in T-cell proliferation and the biochemical mechanisms by which they play these roles, particularly in vivo. The present review focuses on conventional populations of TCR(alpha)beta T cells. Older findings and new insights into the function of specific lymphokines in T-lymphocyte proliferation in vivo are summarized along with unanswered questions raised by these observations. Vital contributions of lymphokines to clonal proliferation arise from two processes: the protection of cells against apoptosis and the activation of cell cycling. Findings are underscored indicating that the activity of a particular lymphokine depends on the subset of T cells (CD4 vs. CD8; naive vs. memory) to which it binds, and that point to potential pitfalls of extrapolating from tissue culture-adapted models to the regulation of T cells in vivo. After summaries of signaling mechanisms related to the proliferative activity of lymphokines, recent findings are highlighted suggesting that such signaling is a regulated and plastic process rather than one fixed schema of action.
Genetic polymorphisms are well-recognized causes of interindividual differences in disease risk and treatment response in humans. For genes containing multiple single-nucleotide polymorphisms (SNPs), haplotype structure is often the principal determinant of phenotypic consequences, and haplotype distribution represents the best approach for assessing patterns of linkage disequilibrium. To permit more widespread molecular determination of haplotypes, we developed a simple yet robust method to determine haplotype structure for multiple SNPs located up to 30 kb apart in genomic DNA using long-range polymerase chain reaction (LR-PCR) and intramolecular ligation. Complete concordance was shown between the new method and conventional approaches, such as family pedigree analysis or cloning and sequencing. The availability of a simple method to directly determine haplotype structure using genomic DNA, without family pedigree analysis, cloning or complex instrumentation, provides an important new tool for elucidating the genetic determinants of drug disposition and effects, disease risk, and molecular evolution.
The central goal of our laboratory is to understand the regulation of lymphoid cells through molecular mechanisms of signal transduction and transcriptional control. A long-standing focus has been on changes that influence the effector function of mature lymphocytes. Work in the laboratory is oriented toward the identification of new regulatory mechanisms using cell lines and primary cells, and the validation of these in vitro findings in mouse models of immune responses and diseases. In this review, we summarize key insights into the regulation of T helper cell function during the phase of immunity where effector responses arise de novo. Particular interest has been centered on cytokine gene regulation as part of T cell differentiation into the Th1 and Th2 subsets. Information on IL-4 receptor signaling and the role of NF-kappaB transcription factors is reviewed. Our more recent work is designed to understand how regulation at the Th1/2 effector stages is related to the control of memory T cell survival, immune recall responses, and the role of these responses in immune-mediated disease.
Chronic inflammatory autoimmune diseases such as diabetes, experimental autoimmune encephalomyelitis, and collagen-induced arthritis (CIA) are associated with type 1 (Th1, Tc1) T cell-dependent responses against autoantigens. Immune deviation toward type 2 (Th2, Tc2) response has been proposed as a potential means of gene therapy or immunomodulation to treat autoimmune diseases based on evidence that type 2 cytokines can prevent or alleviate these conditions. In this report we assessed the effects of elevated type 2 responses on CIA using transgenic mice expressing an IL-2R beta/IL-4R alpha chimeric cytokine receptor transgene specifically in T cells. In response to IL-2 binding, this chimeric receptor transduces IL-4-specific signals and dramatically enhances type 2 responses. In contrast to published reports of Th2-mediated protection, CIA was exacerbated in IL-2R beta/IL-4R alpha chimeric receptor transgenic mice, with increased disease incidence, severity, and earlier disease onset. The aggravated disease in transgenic mice was associated with an increase in type 2 cytokines (IL-4, IL-5, IL-10) and an increase in collagen-specific IgG1 levels. However, IFN-gamma production is not affected significantly in the induction phase of the disease. There is also an extensive eosinophilic infiltration in the arthritic joints of the transgenic animal, suggesting a direct contribution of type 2 response to joint inflammation. Taken together, our findings provide novel evidence that enhancement of a polyclonal type 2 response in immunocompetent hosts may exacerbate an autoimmune disease such as CIA, rather than serving a protective role. This finding raises significant caution with regard to the potential use of therapeutic approaches based on immune deviation toward type 2 responses.
Proliferative responses of lymphoid cells to IL-2 and IL-4 depend on activation of the cells, but the mechanism(s) by which activation enhances cellular competence to respond to cytokines is not fully understood. The NF-kappaB/Rel family represents one signal transduction pathway induced during such activation. We show in this study that inhibition of NF-kappaB through the expression of an IkappaBalpha (inhibitory protein that dissociates from NF-kappaB) mutant refractory to signal-induced degradation (IkappaBalpha(DeltaN)) interfered with the acquisition of competence to proliferate in response to IL-4 as well as IL-2. Thymocytes and T cells from IkappaBalpha(DeltaN) transgenic mice expressed normal levels of IL-2R subunits. However, transgenic cells exhibited a dramatic defect in Stat5A activation treatment with IL-2, and a similar defect was observed for IL-4-induced Stat5. In contrast, T lymphoid cells with inhibition of NF-kappaB showed normal insulin receptor substrate-2 phosphorylation and only a modest decrease in Stat6 activation and insulin receptor substrate-1 phosphorylation after IL-4 stimulation. These results indicate that the NF-kappaB/Rel/IkappaBalpha system can regulate cytokine receptor capacitation through effects on the induction of downstream signaling by the Stat transcription factor family.
Both B and T lymphocytes require ongoing signals to maintain their viability. The pleiotropic cytokine interleukin (IL-) 4 plays an important role in the maintenance of activated T cells, perhaps reflecting induction of the anti-apoptotic genes Bcl-2 and Bcl-X(L). However, it is not known which of the signalling pathways known to link the IL-4 receptor with transcription regulation are required, or if the levels of Bcl-2/X induction under such physiologic conditions are sufficient to account for the anti-apoptotic effects of IL-4. We report here that although blockade of pathways (PI 3-kinase and pp70 S6 kinase) recruited by the IRS-1/2 adaptor proteins inhibited the anti-apoptotic function of IL-4, Bcl-2/X induction were normal. These findings were recapitulated in primary and culture-adapted T cells whose Stat6 signalling pathway also was defective. These results demonstrate that both the Stat6 and PI 3-kinase pathways can be dispensable for Bcl-2/X induction by IL-4, thus suggesting the involvement of an additional signal transduction pathway. Moreover, the preservation of Bcl-2/X induction despite inhibition of the anti-apoptotic function of IL-4 indicates that this cytokine activates additional protective mechanisms.
Copyright 2000 Academic Press.
After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values.039-.0044 for atopy and. 029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.
Strength of T cell receptor (TCR) signaling, coreceptors, costimulation, antigen-presenting cell type, and cytokines all play crucial roles in determining the efficiency with which type 2 T lymphocytes (Th2, Tc2) develop from uncommitted precursors. To investigate in vivo regulatory mechanisms that control the population of type 2 T cells and disease susceptibility, we have created lines of transgenic mice in which expression of a chimeric cytokine receptor (the mouse interleukin 2 receptor beta chain [IL-2Rbeta] extracellular domain fused to the cytoplasmic tail of IL-4Ralpha) is targeted to the T lymphoid lineage using the proximal lck promoter. This chimera transduced IL-4-specific signals in response to IL-2 binding and dramatically enhanced type 2 responses (IL-4, IL-5, and immunoglobulin E production) upon in vitro TCR stimulation or in vivo antigen challenge. Thus, type 2 effector function was augmented by IL-4 signals transduced through a chimeric receptor expressed in a T cell-specific manner. This influence was sufficient for establishment of antigen-induced allergic airway hyperresponsiveness on a disease-resistant background (C57BL/6).
Interleukin (IL)-4 is a cytokine that regulates both the growth and differentiation of hematopoietic cells. Its ligand binding specificity and important signal transduction mechanisms are conferred by the IL-4 receptor alpha chain (IL-4Ralpha). The I4R is a tyrosine-containing motif within IL-4Ralpha that is critical for proliferative responses to IL-4. Although the I4R also contributes to gene regulation, nuclear targets directly regulated by this motif have not been described. It is shown here that the tyrosine at position 497 in the I4R is critical for regulation of the phosphorylation status of a set of nuclear proteins that includes HMG-I(Y), small non-histone chromosomal proteins involved in the control of gene expression in hematopoietic cell lines. Moreover, IL-4 is unable to induce HMG-I(Y) phosphorylation in insulin receptor substrate-1-deficient cells, and the inhibitor wortmannin completely blocks IL-4 regulation of HMG-I(Y) phosphorylation status but not activation of an IL-4 Stat protein. Taken together, these data indicate that HMG-I(Y) is a nuclear target whose phosphorylation status is regulated through the I4R motif via insulin receptor substrate proteins, independent of activation of the Stat pathway.