Fateh Ouaaz

Involvement of cyclic AMP and nitric oxide in immunoglobulin E-dependent activation of Fc epsilon RII/CD23+ normal human keratinocytes.

Epidermal keratinocytes (EK) are exposed to multiple inflammatory stimuli and paracrine factors secreted by various dermal cells (lymphocytes, mast cells, macrophages, fibroblasts) during wounding, cutaneous allergy, and infections. We have previously demonstrated that after stimulation with interleukin 4 or interferon-gamma, human EK express the low-affinity receptor for IgE (Fc epsilon RII/CD23) on their surface. In the present study, we showed that the ligation of CD23 by IgE/anti-IgE immune complexes or specific monoclonal antibody induces a dose-dependent release of interleukin 6 and tumor necrosis factor-alpha from EK. CD23-ligation activates the nitric oxide-dependent pathway, as demonstrated by the high levels of nitrites released in cell supernatants, and the accumulation of intracellular cyclic nucleotides in EK. These second messengers are required for IgE-dependent stimulation of cytokine production by these cells, inasmuch as this is completely abolished by the use of cAMP or nitric oxide synthase antagonists. Human epithelial keratinocytes may thus participate in IgE-mediated immune responses, through their ability to express functional CD23 antigen.

Theophylline, a new inducer of apoptosis in B-CLL: role of cyclic nucleotides

Summary. We report a case of indolent B‐chronic lymphocytic leukaemia (B‐CLL) in a stage A patient, treated for 10 years only by theophylline for bronchial asthma. As suggested by the spontaneous apoptosis in the patients blood (10%), theophylline at 50μg/ml increased spontaneous apoptosis after 72 h in culture by a mean percentage of 90% (range 79‐98%) in six B‐CLL cases studied in vitro. This effect was partially reversed with Rp‐cAMP. a cAMP antagonist, which implies a potent role for this second messenger. We describe a new property of theophylline. which might be an alternative treatment in B‐CLL.

Ligation of CD23 activates soluble guanylate cyclase in human monocytes via an L-arginine-dependent mechanism.

Transduction through FcR2/CD23 was analyzed in normal human monocytes using immunoglobulin E (IgE)‐anti‐IgE immune complexes (IgE ICs) and monoclonal antibodies (mAbs) to CD23. Anti‐CD23 mAb and IgE IC triggered a time‐dependent increase in cGMP and cAMP in interleukin‐4–preincubated (CD23+) but not in unstimulated (CD23‐) monocytes. Maximal cGMP and cAMP accumulations were observed 10 and 20 min, respectively, after the onset of CD23 ligation. The increase in cGMP was inhibited with N ω‐monomethyl‐l‐arginine (L‐NMMA), which also partially affected cAMP accumulation. Addition of an anti‐CD23 mAb Fab fragment inhibited the IgE IC– and the anti‐CD23 mAb–induced cGMP and cAMP accumulation, confirming the engagement of CD23. In addition, IgE IC and anti‐CD23 mAb induced, at least in some donors, a production of nitrite that was inhibited in the presence of L‐NMMA. Taken together, these findings suggest a possible involvement of the nitric oxide synthase pathway in IgE IC–mediated activation of CD23+ monocytes. J. Leukoc. Biol. 57: 160–167; 1995.

Interleukin 4 inhibits the proliferation and promotes the maturation of human leukemic early B cells

Abstract:  The effects of interleukin 4 (IL‐4) on human leukemic precursor B‐cell lines were investigated. Recombinant IL‐4 (rIL‐4) was added to three acute lymphoblastic leukemia‐derived pre B‐cell lines: Reh, Km3 and Nalm‐6. Our results show that rIL‐4 significantly decreases continuous proliferation of Reh and Km3 cells while Nalm‐6 cells have a limited response in this respect. This rIL‐4 effect is dose‐dependent and can be neutralized by anti‐IL‐4 monoclonal antibody (mAb). Furthermore, rIL‐4 down‐regulated IL‐3‐induced proliferation of Reh cells. Phenotypic analysis of rIL‐4‐treated cells points to significant induction of surface marker maturation of leukemic cells by this cytokine. Together, these in vitro data suggest that IL‐4: 1) inhibits the proliferation and 2) promotes the differentiation of certain human leukemic B‐cell precursors.