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FcRIIA and FcRIIIB Mediate Nuclear Factor Activation through Separate Signaling Pathways in Human Neutrophils ¹

Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico

Receptors for IgG Abs (Fc receptors) are capable of triggering diverse cell responses in leukocytes. In neutrophils, two Fc receptors, namely FcRIIA and FcRIIIB, are constitutively expressed. The signaling pathways that regulate FcRIIA-mediated phagocytosis have been relatively well described. However, the different signaling pathways that lead to NF activation after engagement of each Fc receptor have only been partially described. To address this problem, neutrophils were stimulated by cross-linking selectively each type of Fc receptor with specific mAbs, and NF activation was then analyzed. FcRIIIB, but not FcRIIA, promoted a robust increase in phosphorylated ERK in the nucleus, and also efficient phosphorylation of the NF Elk-1. Complete mAb 3G8 (anti-FcRIIIB) induced a higher response than did F(ab')₂ fragments of mAb 3G8, suggesting a possible synergistic effect of both FcR receptors. However, mAb IV.3 (anti-FcRIIA) alone did not cause an increase of phosphorylated ERK in the nucleus. FcRIIIB-induced nuclear phosphorylation of ERK, and of Elk-1, was not affected by Syk, PI3K, or MEK inhibitors. In contrast, FcRIIA- or FcRIIIB-mediated phosphorylation of cytoplasmic ERK depended on Syk, PI3K, and MEK. Also, ERK, but not MEK, was constitutively present in the nucleus, and FcRIIIB cross-linking did not increase the levels of nuclear ERK or MEK. These data clearly show that different neutrophil Fc receptors possess different signaling capabilities. FcRIIIB, but not FcRIIA, activates a unique signaling pathway leading to the nuclear-restricted phosphorylation of ERK and Elk-1, independently of Syk, PI3K, or MEK.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant 48573-M from Consejo Nacional de Ciencia y Tecnología, Mexico, and by Grant IN212308 from Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México, Mexico.

² Address correspondence and reprint requests Dr. Carlos Rosales, Department of Immunology, Department of Immunology, Instituto de Investigaciones Biomédicas-Universidad Nacional Autónoma de México, Apartado Postal 70228, Ciudad Universitaria, México D.F.-04510, Mexico. E-mail address: carosal{at}servidor.unam.mx

³ Abbreviation used in this paper: PMN, peripheral blood human neutrophils.

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