Mechanism of Interleukin-2 Signaling: Mediation of Different Outcomes by a Single Receptor and Transduction Pathway

Tigges, Michael; Casey, Leslie S.; Koshland, Marian Elliott

doi:10.1126/science.2492678

Cited by 144 publications

(48 citation statements)

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“…Interleukin-2 (IL-2) is aT cell-derived cytokine involved in the proliferation and differentiation of T lymphocytes, B lymphocytes, NK cells as well as monocytes [1][2][3][4]. Upon antigen recognition by T lymphocytes, the induction of both IL-2 and IL-2R gene expression allows subsequent proliferation of activated clones, either in an autocrine or paracrine fashion [1,5].…”

Section: Introductionmentioning

confidence: 99%

Role of LFA‐1/ICAM‐1 in interleukin‐2‐stimulated lymphocyte proliferation

et al. 1993

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Major adhesion routes between lymphoid cells involve the receptor/ligand pairs LFA-l/ICAM-1 and CD2/LFA-3, in addition to VLA or CD44 molecules. In this study we evaluated the role of these adhesion receptors in the proliferative response of lymphoid cells to interleukin-2 (IL-2). Blocking studies were performed with a panel of monoclonal antibodies (mAb) directed against these adhesion molecules. Selective inhibition of recombinant (r)IL-2-induced cell proliferation was observed with mAb directed against the a or ¡3 subunit of LFA-1 or to its ligand ICAM-1. Interestingly, rIL-2-induced proliferation was also inhibited by NKI-L16, an anti-la antibody known to enhance cell-cell interac tion. Resting lymphocytes were preferentially susceptible to the inhibition, particularly in an early phase of culture and when stimulated with a relatively low dose of rIL-2. By using mAb that specifically could block distinct rIL-2 activation pathways, LFA-l/ICAM-1 interaction was found to be required for p55 IL-2 receptor (IL-2R)-mediated interaction of rIL-2 with its high-affinity receptor, but not for p75 IL-2R-rnediated responses. Furthermore, it was shown that the rIL-2 response of T lymphocytes, but not of natural killer cells, was dependent on LFA-l/ICAM-1 interaction. This suggests that LFA-l/ICAM-1 interaction is required for an optimal iiL-2 response of cells capable of IL-2 secretion. Our data provide evidence for the hypothesis that adhesion receptor-directed release of IL-2 may result in a locally high concentration of IL-2 that triggers high-affinity IL-2R signaling and up-regulates p55 IL-2R to enhance cytokine responsive ness.

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Section: Introductionmentioning

confidence: 99%

Role of LFA‐1/ICAM‐1 in interleukin‐2‐stimulated lymphocyte proliferation

et al. 1993

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“…The p55 chain binds IL-2 with a low affinity (Kd ti10 -g M), the p70-75 chain binds IL-2 with an intermediate affinity (Kd N10'9 M), and both molecules form a noncovalently linked heterodimer that binds IL-2 with high affinity (Kd _10 -12 M) . The response of T or B cells to IL-2 seems to be mediated by p70-75 and not p55 (5,6) . Human monocytes respond to IL-2 with induction of IL-1 mRNA (7), development oftumoricidal activity (2), and we have recently shown that IL-2 enhances c-fms mRNA expression (Espinoza-Delgado et al, manuscript submitted).…”

mentioning

confidence: 99%

Expression and role of p75 interleukin 2 receptor on human monocytes.

Espinoza‐Delgado

Ortaldo

Winkler‐Pickett

et al. 1990

The Journal of Experimental Medicine

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of Medicine, Sendai 980 fapan IL-2, initially discovered for its mitogenic activity on T cells (1), also acts on monocytes (2) . T and B cells express at least two forms of IL-2 receptor (IL-2R): the p55 glycoprotein (IL-2Rtx), which is recognized by the anti-Tac mAb (3), and the p70-75 kD glycoprotein (IL-2RO), which reacts with the TU27 mAb (4) . The p55 chain binds IL-2 with a low affinity (Kd ti10 -g M), the p70-75 chain binds IL-2 with an intermediate affinity (Kd N10'9 M), and both molecules form a noncovalently linked heterodimer that binds IL-2 with high affinity (Kd _10 -12 M) . The response of T or B cells to IL-2 seems to be mediated by p70-75 and not p55 (5, 6) . Human monocytes respond to IL-2 with induction of IL-1 mRNA (7), development oftumoricidal activity (2), and we have recently shown that IL-2 enhances c-fms mRNA expression (Espinoza-Delgado et al., manuscript submitted). The ability of human monocytes to respond to IL-2 indicates the presence of a functional receptor for IL-2 on these cells . However, fresh human monocytes do not express Tac antigen (8), and there are no reports concerning the expression of p70-75 on fresh or IL-2-treated monocytes . We have investigated the surface expression ofp70-75, and its potential role in the cytotoxic response of monocytes to IL-2, using the anti-p75 mAb TU27 (4) . We demonstrated that human monocytes express constitutively high levels of p75 and that TU27 mAb blocks the activation to a cytolytic stage induced by IL-2 but does not block IFN-y-induced, monocyte-mediated cytolysis . Materials and MethodsCell Culture. Monocytes were purified from leukophoresed PBMC by centrifugal elutriation (9) . The purity of the monocyte preparation used in these studies was 93 t 3 % as assessed by morphology on Giemsa-stained cytocentrifuge preparations and flow cytometry using the monocyte-specific mAb Leu M3 . Cells were cultured in RPMI 1640 (Advanced Biotechnology, Inc ., Columbia, MD), containing penicillin 100 U/ml, streptomycin 100 Ag/ml, 2 MM t.-glutamine, 20 mM Hepes (Gibco Laboratories, Grand Island, NY) and 10% heatinactivated FCS (HyClone Laboratories, Logan, UT) . Recombinant human IL-2 was kindly provided by Cetus Corp., Emeryville, CA . Recombinant human IFN-y was kindly provided by Genentech, Inc ., South San Francisco, CA . LPS levels were less than 12 pg/ml in all reagents and media used .

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“…Because it is reported that IL-4 does not induce Ca2+ mobilization or protein kinase C activation (28), IL-4 and PMA inhibit IL-5-mediated BCL1-B20 cell differentiation in a different intracellular mechanism. Consequently, it would be interesting to use IL-4 and PMA as inhibitors for IL-5-induced IgM secretion and IL-5-induced signaling.…”

Section: Discussionmentioning

confidence: 99%

Elevated Expression of Proto‐Oncogenes during Interleukin‐5‐Induced Growth and Differentiation of Murine B Lineage Cells

Migita

Yamaguchi²,

Katoh³

et al. 1990

Microbiology and Immunology

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Interleukin 5 (IL-5), a lymphokine produced by helper T cells, is involved in the regulation of growth and differentiation of B cells and other hematopoietic cells. To elucidate IL-5-mediated intracellular mechanisms, we have established. IL-5-dependent and -independent murine early B cell lines, J6 and MJ88-1, respectively, and examined the effect of IL-5 on the expression of proto-oncogenes during proliferation. Two-to 3.5-fold increases in the levels of c-myb, c-myc, c-fos, and mRNA were observed in J6 cells, compared with those in MJ88-1 cells. Further, a role of IL-5 in the proto-oncogene expression during differentiation was examined by using thymidine-treated murine B-cell chronic leukemia BCL1-B20 cells with growth arrest.After 4-day culture, the amount of IgM secreted from BCL1-B20 cells was augmented 4-6 fold in the presence of IL-5.Although expression of c-myb, c-fos, and c-fms mRNA did not change, only c-myc mRNA expression was elevated within 30 min of stimulation with IL-5 and reached a maximal level by 1 hr. Addition of phorbol 12-myristate 13-acetate (PMA) or IL-4 to the culture of BCL1-B20 cells inhibited both the IL-5-mediated augmentation of IgM secretion and the elevated expression of c-myc mRNA.These findings suggest that the IL-5 signal may be associated with the up-regulation of c-myc expression.Recently, proto-oncogenes have been in the forefront of potential factors involved in proliferation and differentiation of hematopoietic progenitor cells. The increased expression of c-myc, c-fos, and c-myb proto-oncogenes has been shown in the growth factor-induced proliferation of various cells including normal human T, B cells and mouse fibroblasts (9,15,26). In contrast, decreased expression of c-myc, c-myb proto-oncogenes was observed during the differentiation of human cell lines, HL-60, and U-937 into granulocytes and monocytes, respectively (5, 31).Interleukin-5 (IL-5) is a T cell-derived soluble factor that enhances the proliferation and differentiation of B cells as well as eosinophils (21,27,35). Cloning of cDNA for murine IL-5 and production of monoclonal antibodies against IL-5 937

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Mechanism of Interleukin-2 Signaling: Mediation of Different Outcomes by a Single Receptor and Transduction Pathway

Cited by 144 publications

References 50 publications

Role of LFA‐1/ICAM‐1 in interleukin‐2‐stimulated lymphocyte proliferation

Role of LFA‐1/ICAM‐1 in interleukin‐2‐stimulated lymphocyte proliferation

Expression and role of p75 interleukin 2 receptor on human monocytes.

Elevated Expression of Proto‐Oncogenes during Interleukin‐5‐Induced Growth and Differentiation of Murine B Lineage Cells

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