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Costimulation of Resting B Lymphocytes Alters the IL-4

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Costimulation of Resting B Lymphocytes Alters the IL-4 Cell Research, (2001); 11(1):44-54 Costimulation of resting B lymphocytes alters the IL-4-activated IRS2 signaling pathway in a STAT6 independent manner: impli- cations for cell survival and proliferation ZAMORANO JOSE*, ANN E KELLY, JONATHAN AUSTRIAN, HELEN Y WANG, ACHSAH D KEEGAN** Department of Immunology, Jerome Holland Labs, American Red Cross, Rockville, MD, USA ABSTRACT IL-4 is an important B cell survival and growth factor. IL-4 induced the tyrosine phosphorylation of IRS2 in resting B lymphocytes and in LPS- or CD40L-activated blasts. Phosphorylated IRS2 coprecipitated with the p85 subunit of PI 3' kinase in both resting and activated cells. By contrast, association of phosphory- lated IRS2 with GRB2 was not detected in resting B cells after IL-4 treatment although both proteins were expressed. However, IL-4 induced association of IRS2 with GRB2 in B cell blasts. The pattern of IL-4- induced recruitment of p85 and GRB2 to IRS2 observed in B cells derived from STAT6 null mice was identical to that observed for normal mice. While IL-4 alone does not induce activation of MEK, a MEK1 inhibitor suppressed the IL-4-induced proliferative response of LPS-activated B cell blasts. These results demonstrate that costimulation of splenic B cells alters IL-4-induced signal transduction independent of STAT6 leading to proliferation. Furthermore, proliferation induced by IL-4 in LPS-activated blasts is de- pendent upon the MAP kinase pathway. Key words: B lymphocytes, IL-4, survival, proliferation. INTRODUCTION Interleukin-4 (IL-4), a cytokine produced by T The inappropriate enhancement of lymphocyte cells, mast cells, and basophils, has profound ef- survival due to a block in programmed cell death fects on the growth and differentiation of B and T and/or an enhancement of entry into the cell cycle lymphocytes[3]. As an important growth and sur- can contribute to the abnormal expansion of clones vival factor for normal B cells, IL-4 maintains the resulting in tumorigenesis or the breakdown of pe- viability of small, resting B cells, but is unable to ripheral self-tolerance[1],[2]. Proper lymphocyte induce cellular proliferation without a co-stimula- homeostasis is critical for normal immune function tory agent such as bacterial lipopolysaccharide (LPS) and is maintained by a complex series of cellular or CD40 stimulation[4-6]. Additionally, IL-4 has interactions and the action of secreted cytokines. been shown to reverse the effects of certain stimuli that inhibit B cell activation, such as tolerogenic * Current address: Unidad de Investigacion, Hospital San Pedro de doses of anti-IgM[7],[8], the cross-linking of sur- Alcantala, Avda Millan Astray, 10003 Caceres face IgM and Fc receptors[9], and the susceptibil- ** Address correspondance to: Dr.Achsah D. Keegan, Immunology Department, Jerome Holland Laboratories, American Red Cross, ity of CD40L-activated B cells to FasL-mediated 15601 Crabbs Branch Way, Rockville, MD 20855, (301) 517-0326, death[10]. Although major advances have been Fax: (301) 517-0344, E-mail: [email protected] made in understanding the structure of the IL-4 Abbreviations: IL-4, interleukin-4; JAK, Janus kinase; STAT6, sig- nal transducer and activator of transcription 6; IRS, insulin recep- receptor complex and the biochemical signaling tor substrate; GRB2, growth-factor receptor bound protein 2; pathways that are activated by the binding of IL-4 MAPK, mitogen activated protein kinase; ERK, extracellular sig- to its receptor[11], most of these pathways have nal regulated kinase; MEK, mitogen protein kinase. Received Nov- 8-2000. Revised Dec-26-2000. Accepted Jan-9-2001. been analyzed in long-term factor-dependent lines. Zamorano J et al The mechanism by which IL-4 signals in normal pathway. However, the ability of IL-4 to activate lymphocytes is still unclear. this pathway is controversial [reviewed in 11]. A IL-4 binds to a cell surface receptor complex number of studies have found that IL-4 does not consisting of the IL-4 binding chain (IL-4R ) and stimulate the tyrosine phosphorylation of SHC, the either the common γ chain (γc) or a component of activation of ras, the phosphorylation of raf, or the the IL-13 receptor (IL-13Rα)[12]. The IL-4Ra as- tyrosine phosphorylation of extracellular signal sociates with the Janus family kinase JAK1 and regulated kinase (ERK)[11,21]. There are some the γc associates with JAK3[13-15]. Occupancy of studies, however, that show several cell lines do the IL-4 receptor induces tyrosine phosphorylation respond to IL-4 with weak tyrosine phosphoryla- of the IL-4R γ itself and of a 170-180 kDa protein, tion of SHC and ERK[11,21]. operationally defined as IL-4-induced phosphory- Overexpression of IRS1 has been shown to pro- lated substrate, 4PS, in many IL-4-responsive cell tect 32D cells from death induced by IL-3 depriva- types[16]. 4PS was termed IRS2 due to its homol- tion[22]. The IRS1-dependent prevention of ogy to the insulin receptor substrate-1 (IRS1), a apoptosis was associated with the activation of PI substrate of the insulin receptor kinase[17,18]; 3' kinase since wortmannin and LY294002, two both substrates act as important signaling mol- inhibitors of PI 3' kinase[23,24], partially inhibited ecules for the IL-4, insulin and insulin-like growth the protection from apoptosis mediated by IL-4. In factor-I (IGF-I) receptors[18]. addition, it has been shown that treatment of small, IRS1 and IRS2 are not highly homologous at the resting B cells with IL-4 results in the potent ty- DNA level, but they contain localized regions of rosine phosphorylation of a 180 kDa protein that high homology at the amino acid level[18]. Both is precipitated by IRS2-specific antisera, but not contain numerous potential tyrosine phosphoryla- by IRS1 specific antisera[22],[25]. Furthermore, tion sites and numerous potential serine/threonine wortmannin and LY294002 blocked the protection phosphorylation sites. Tyrosine phosphorylation of from spontaneous apoptosis by IL-4[22] suggest- sites within both IRS1 and IRS2 allows their high ing the IRS2/PI 3 -kinase pathway is important affinity association with cellular proteins that con- for the IL-4-induced protection of normal B cells tain SH2 domains including the p85 regulatory from apoptosis. Indeed, resting B cells purified from subunit of PI 3' kinase (PI-3K), growth-factor re- mice lacking expression of the p85a subunit of PI ceptor-bound protein 2 (GRB2), and the src-ho- 3' kinase in the lymphocyte compartment were not mology protein tyrosine phosphatase 2 (SHP2), as protected from apoptosis by IL-4[26]. well as other signaling molecules. The precise role The role of STAT6 in the regulation of B-cell of these recruited signaling molecules in regulat- proliferation and protection from apoptosis in re- ing responses to IL-4 is not well understood. sponse to IL-4 is unclear. Several lines of evidence Previous studies, focusing on the IL-3-depen- indicate that the activation of two major biochemi- dent myeloid progenitor cell type 32D, support a cal pathways, IRS and STAT6, by IL-4 are inde- role for IRS family members in signaling the IL-4- pendent of each other at the induction stage of the induced proliferation and prevention of apoptosis. signal transmission. In 32D cells lacking IRS1 or 32D cells expressing the cDNA encoding IRS1 or IRS2 expression, IL-4-treatment is able to activate IRS2 (32D-IRS) are able to mount a mitogenic re- STAT6 DNA-binding activity[27]. On the other sponse to IL-4[18,19], while 32D cells lacking IRS hand, IL-4 is able to stimulate the tyrosine phos- expression are not. In these transfected cells, IL-4 phorylation of IRS2 in lymphocytes derived from readily induces the tyrosine phosphorylation of IRS mice deficient in STAT6 expression as well as in and its association with p85 and GRB2; a prolif- lymphocytes derived from normal mice[28]. Sev- erative response to IL-4 has been associated with eral reports suggests that STAT6 may not contrib- IRS docking to GRB2[20]. The adaptor GRB2 binds ute to the IL-4-induced survival of T cells[29,30]. to the protein encoded by son-of-sevenless, SOS, While the early biochemical pathways activated by the nucleotide exchange factor that regulates the IL-4 are distinct, new evidence suggests that they Ras/Raf/mitogen activated protein kinase (MAPK) may overlap further downstream leading to coop- 45 Costimulation alters the IL-4-activated IRS2 pathway eration in a final biologic outcome. Three indepen- containing recombinant CD40L (a generous gift of Dr. Marilyn dent laboratories showed that STAT6 null mice Kehry, Boehringer Ingelheim) for 48 h at 37 oC. Recombinant have a modest to substantial diminution in IL-4- mIL-4 was obtained from R and D Systems (Minneapolis, MN). Wortmannin was purchased from Sigma (St Louis, MO). induced co-stimulation of B and T cell growth[31- LY294002, PD98059, and SB203580 were obtained from 33] in response to antigen receptor cross-linkage Calbiochem. suggesting that STAT6 is involved in regulating the proliferative response. Apoptosis assay While there are many analyses of IL-4 signal Percentage of apoptotic cells was determined by analyzing transduction in long-term cell lines and a few us- the nuclear DNA content by flow cytometry[34]. Splenic cells ing primay T cells[11], there is only limited infor- were stained with FITC-conjugated anti-B220 monoclonal anti- mation on the molecular mechanism of IL-4 sig- body (Pharmigen, San Diego, California). After washing in PBS, o naling in normal B lymphocytes. To characterize the cells were incubated overnight in 75% ethanol at 4 C.
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