Disease relevance of Il2

• Abrogation of IL-3 and IL-2 dependence by recombinant murine retroviruses expressing v-myc oncogenes [1].
• Antibody blockade of IL-2 but not IL-4 reverses the marked reduction of lymph node V beta 8+ T cells caused in mice by the bacterial superantigen Staphylococcus aureus enterotoxin B. IL-2 may thus participate in a feedback regulatory mechanism by predisposing mature T lymphocytes to apoptosis [2].
• The gamma chain of the interleukin-2 (IL-2) receptor is shared with the functional IL-4 receptor and is causatively related to X-linked severe combined immunodeficiency (XSCID), which is ascribed to a profound T cell defect [3].
• Interferon gamma is involved in the recovery of athymic nude mice from recombinant vaccinia virus/interleukin 2 infection [4].
• Interleukin 2 (IL-2) production was studied in a subclone of the murine thymoma EL 4 [5].
• Spleen cells from newborn mice are immunologically nonreactive and do not respond by proliferation upon stimulation with the T cell mitogen concanavalin-A (Con-A) or with IL-2, but they synthesize a of mRNA for IFNγ after stimulation with IL-2, but do not synthesize IFNγ upon stimulation with Con-A. Since IFNγ is of prime importance for antiviral and fungicidal activities and has complex regulatory functions for the cells of the immune system, we suggest that it could play an important role in the survival of newborns [6].

Psychiatry related information on Il2

• Influence of acute and repeated interleukin-2 administration on spatial learning, locomotor activity, exploratory behaviors, and anxiety [7].
• CONCLUSIONS: These results suggest that elevated TNF-alpha may be one mechanism for the sustained elevated leptin observed in IL-2(-/-) mice during food deprivation [8].
• Different effects of IL-2 in vivo treatment and emotional stress on POMC gene expression in the pituitary of mice [9].
• OBJECTIVES: Major depression is associated with increased circulating interleukin-2 (IL-2) levels, and IL-2 immunotherapy may provoke depressive symptoms, leading to the suggestion that this cytokine may contribute to the evolution of affective disorders [10].
• In vitro studies indicate that bridging the TCR/CD3 complex of resting T cells with tumor IgM Id and the appropriate bispecific antibody induced proliferation and secretion of IL-2 [11].

High impact information on Il2

• High concentrations of antigen (or anti-TCR mAb) inhibit IL-2-induced proliferation (but not lymphokine production) by TH1 and cytolytic T lymphocyte (CTL) clones only [12].
• The general impression is that CD8+ cytotoxic T lymphocytes, CD4+ TH1 cells, gamma interferon, and IL-2 are of major importance, with these different components of the immune system interacting to promote an optimal response [13].
• QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing Il2 [14].
• Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation [15].
• By this approach, two retroviral producer cell lines encoding cytokines (IL-4 and IL-2) directed tumoricidal inflammatory responses to established metastases [16].

Chemical compound and disease context of Il2

• Lymphoblasts arising through stimulation by Escherichia coli lipopolysaccharide failed to express IL-2 receptors [17].
• Bacillus Calmette-Guérin plus interleukin-2 and/or granulocyte/macrophage-colony-stimulating factor enhances immunocompetent cell production of interferon-gamma, which inhibits B16F10 melanoma cell growth in vitro [18].
• Intratumoral treatment of established C6 glioma with recombinant viruses rVV-p53, rVV-mIL2, rVV-mIL12, and rVV-2-12 induced the prolonged expression of p53, IL-2, IL-12, and both cytokines simultaneously [19].
• The results showed that, compared to Tris-EDTA buffer (TE, 1mM Tris, 0.1mM EDTA, pH 8.0) injected mice, the expressions of Th1 type cytokine IFN-gamma, IL-2 and IL-12 were increased in hybrid phage, KLH-C, and wild phage immunized mice, and there were no differences between mice immunized with hybrid phage and KLH-C [20].
• These findings suggest a MEL action to decrease metastasis mediated by a possible interplay between zinc and MEL, via corticosterone, with consequent restoration of thymic efficiency and IL-2 production [21].

Biological context of Il2

• We report here the mapping of Aod2, the locus that controls this phenotype, to mouse chromosomes 3 within a region encoding Il2 and Fgfb [22].
• To investigate whether sequence variation exists in the promoter region of the Il2 gene, which might alter its expression, we sequenced the promoter region of the Il2 gene from mouse strains carrying either an Idd3 susceptibility or resistance allele [23].
• During Ag stimulation of T cells, the recognition of B7 molecules by the CD28 costimulatory receptor increases the level of c-Fos, a component of the AP-1 transactivator known to bind the 5' Il2 gene enhancer [24].
• Using this approach, we localized the Idd3 locus to a 0.35-cM interval on chromosome 3 containing the Il2 gene [25].
• These data, taken together with the immunomodulatory role of IL-2, provide circumstantial evidence in support of the hypothesis that Idd3 is an allelic variation of the Il2 gene, or a variant in strong linkage disequilibrium [25].

Anatomical context of Il2

• Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro [26].
• This is in contrast to the known requirement for IL-2 in NK cell growth [27].
• More recently, there has been evidence for the involvement of IL-2 per se in the stimulation of B-cell growth (ref. 10 and T. Kishimoto and J. Vilcek, personal communications) [28].
• Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling [29].
• Treatments of euthymic mice with high-dose IL-2 also induced transcription of the alpha chain gene in 41% of the non-B blast lymphocytes, but only background percentages of the NK1.1+ cells expressed the alpha chain gene [30].

Associations of Il2 with chemical compounds

• The longest cDNA insert encodes a polypeptide of 169 amino acids, containing unique repeats of a CAG sequence which would encode 12 consecutive glutamine residues within the active IL-2 molecule [28].
• Both asialo-GM1+ (NK) and asialo-GM1- (non-NK) cells were participants in the IFN-gamma-mediated recovery of nude mice from infection with the IL-2-encoding VV recombinant [4].
• Mature CD8+ T cells of lymph nodes can also be activated in ITLB medium plus retinol, provided that interleukin 2 (IL-2) is added [31].
• Functional coupling of the src-family protein tyrosine kinases p59fyn and p53/56lyn with the interleukin 2 receptor: implications for redundancy and pleiotropism in cytokine signal transduction [32].
• Media conditioned by hybridoma cells, even at high dilutions (1:1,000) support the growth of lipopolysaccharide-stimulated B-cell blasts but not that of T-cell growth factor (TCGF)-reactive T-cells [33].

Physical interactions of Il2

• Proteins with bulky or basic substitutions at residue D34 were weak antagonists due to severely reduced IL-2 binding and their reduced binding paralleled their defects in IL-2R activation [34].
• IL-2 induced the binding of Stat5a and b proteins to the human GASd element [35].
• Binding data and Scatchard analysis support these results and show an increase from 3100 to 17,620 low-affinity IL-2 binding sites per cell without any change in affinity after induction of M1 cells by the combination of IL-6 and IL-1 [36].
• The results presented demonstrate that IL-2 signal transduction results in the functional uncoupling of the TCR complex through altering the subcellular distribution of kinase-active Lck [37].
• The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals [38].

Enzymatic interactions of Il2

• Shc was found to be tyrosine-phosphorylated upon IL-2 stimulation in CTLL-20 cells [39].
• This increased proliferation by Tssc6-deleted T lymphocytes was due to increased interleukin 2 production following T-cell receptor stimulation [40].

Regulatory relationships of Il2

• Nuclear factor of activated T cells (NFAT) is a transcription factor that regulates expression of the cytokine interleukin-2 (IL-2) in activated T cells [41].
• Exogenous recombinant (r)IL-2 only partially reverses NOD thymocyte proliferative unresponsiveness to anti-CD3, and this is mediated by the inability of IL-2 to stimulate a complete IL-4 secretion response [42].
• In contrast, recombinant IL-2 induced IL-5 mRNA expression but did not induce detectable expression of IL-4 or granulocyte-macrophage colony-stimulating factor mRNA [43].
• The combination of IL-18 plus IL-2 or IL-12 up-regulates IFN-gamma gene expression and NK cytotoxicity and has synergistic antitumor activity in vivo and in vitro [44].
• Stem cell factor enhances interleukin-2-mediated expansion of murine natural killer cells in vivo [45].

Other interactions of Il2

• Interestingly, the two lymphokines differed in that IL-2, but not BSF-1, induced a lytic population in cultures of unprimed cells without an overt antigenic stimulus [46].
• IL-15 and IL-2: a matter of life and death for T cells in vivo [47].
• In response to mitogenic signals, peripheral T cells in Jak3-deficient mice did not proliferate and secreted small amounts of IL-2 [48].
• Interestingly, the cytokines IL-2 and IFN gamma were minimally affected [49].
• Correspondingly, Stat5a-/- splenocytes exhibited markedly decreased proliferation to IL-2, although maximal proliferation was still achieved at IL-2 concentrations high enough to titrate intermediate-affinity IL-2R beta/gamma(c) receptors [50].

Analytical, diagnostic and therapeutic context of Il2

• Because so much of the work on IL-2 has been done in the human and mouse, we sought to obtain cDNA encoding murine IL-2, and we now report the cloning, expression and sequence analysis of murine IL-2 cDNAs [28].
• IL-2, IL-4, and tumor necrosis factor beta (IFN beta) comprised the third group and these cytokines were expressed only in allogeneic grafts after transplantation [51].
• Flow cytometry indicated that TPA and its related phorbol esters cause a perturbation in the cycling of the cell which may be related to increased IL-2 production [5].
• Vaccination with B16 cells producing IL-4 or gamma-interferon had no effect, and vaccination with B16 cells producing IL-2 decreased survival time [52].
• This activity, herein designated B-cell growth factor (BCGF), has a Mr of approximately equal to 20,000 and it can readily be separated from TCGF (Mr approximately equal to 30,000) by gel filtration [33].

References