Scam/. J. fmmufioi 33, 631-640. 1991 The Response of Human B Cells to Inlerleukin 4 is Determined by their Stage of Activation and Differentiation D W. MAHER, BEVERLEY L. PIKE & A. W. BOYD The Waller and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Parkville. Victoria. Australia Malicr. D, W.. Pike. BCVLTII:> L. & Boyd. A.W. The Response of Human B Cells lo Inlcrloiikin 4 is Delerniincd by ihcir Stage of Aclivation and Ditferenliaiion Smiul. J. Immiimi 33, h.H MO. 1991. ThecRcct orpurifiedrecombinanl humanintcrlcukin 4 (lL-4)on pmlircraiion und IgM secretion of normal and malignant luimiin B eells was studied. IL-4 was found lo co-siimulate the prolil'eraiion ofspicnic B fells in the presence oTanli-lgeotipIed io polyacrylamide beads (anii-lg beads) for a period of 4 days, Incontrasl. IL-4 had litlleeo-stimulalory elTecl on ihe proliferalive response o\ splenic B cells to Ihe more potent mitogen Suiphyloioctus uureus Cowan strain 1 (SAC). Moreover. [L-4 inhibited intcrleukin 2 (IL-2)-induccd proliteraiion of cells eo-stimulaied wilh SAC MiUigen-indueed pre-aclivation of B cells in the presence of IL-4 resulted in a reduction in subsequent IL-2-induced IgM secretion without significantly afiecling prolircration. Human B-cell tumours were also cultured over a 2 3 day period in ihe presence ofanii-lg beads plus lL-2.or lL-4orb<)tli Il.-2and IL-4. IL-4 inhibited ILO-induced proliferation in allcasesof B-cell chronic lymphocytic leukaemia (B-CL.L| and ihe inajorily of cases of low-graiie lymplioma (LCiL) and hairy cell leukaemia (MCL). These findings suggest that IL-4 has stimulatory actions on resting B cells, tiiosi evidcni in the presence of subma.ximal co-milogenic signals, and inhibitory aclions on activated B cells, especially antagonism of Ihe etTects of IL-2. Dr D. W. Mailer. The Waiter and Eliza Hail Insiiluie of Medical Research. Post Office. The Royal Methourne Hospiial. Parkvillc. Vkloria SO.'<<I. .Auxiralia Human interleukin 4 (IL-4) is a 20-kDa protein shown to be secreted by activaied T celLs after a cDNA encoding this molecule was cloned by homology with murine lL-4 [25]. The clTecls o\' IL-4 on human Bcellsincludelhe induction ofthe (.023 surface tnolecule (KCT. receptor) [2]. switch to IgE secretion in the presence ofinterleukin 5 or T cells [)7. 18. 24). and enhanced expression of surface IgM [21] and intercellular adhesion mol- ecules [20). IL-4 has been reported Io have both growth promoting (5J and growth inhibitory [4. 10] influences on B cells while either enhancing \y\. maintaining [4], or inhibiting [10] secretion of IgM and IgG. DetVance ci ul. [5] have reported that IL-4 co-stimulated uith insolubilised anti- lgM to promote the proliferation of resting human B cells and B cells pre-activatcd with cither anti-Ig beads for 1 day or SAC for .^ days. They also reported that I L-4 could inhibit inter- leukin 2 ([L-2)-induced proliferation of pre- activated human B cells but not their differentia- tion to IgM and IgG secreting ceils. Jelinek & Lipsky [10] have shown that proliferation induced by lL-2 acting with SAC was inhibited by IL-4. Moreover, they reported thai the presence of IL-4 during SAC prc-iictivation profoundly suppressed both the subsequent proliferative and differentiative response to IL-2. Inhibitory effects of IL-4 have also been reported on the prolifer- ation of B-ccll chronic lymphocytic leukaemia {B- CLL) cells [12. 15]. The apparent contradiction in the literature of IL-4 being on the one hand a B-eell stimulatory factor and on the other, an inhibitor of IL-2- induced growth of normal and malignant human B cells prompted the present studies. We defme the importance of the nature of activation of normitl B cells in determining their response to IL-4 and show the timing of exposure to IL-4 influences subsequent responses. Also, the re- 631