FcγR receptors activate MAP kinase and up-regulate the cyclooxygenase pathway without increasing arachidonic acid release in monocytic cells

Abstract

THP‐1 monocytic cells were stimulated with IgG‐ovalbumin equivalence immune complexes (IC) and mAb reacting with both FcγRI and FcγRIIA. All of these stimuli were capable of activatingthe cells; however, different patterns of response were observed as regards activation of the p42‐MAP / ERK kinase, triggering of the NF‐κB / Rel system, production of chemotactic cytokines, and induction of the expression of cyclooxygenase‐2 (COX‐2). Activation of p42‐MAP / ERK kinase was a constant finding, which occurred regardless of the type of stimulus applied, for instance, homotypic stimulation of a single type of receptor by cross‐linking with specific mAb or heterotypic stimulation with both types of antibodies and IC. However, the activation of the MAP / ERK kinase cascade was not connected to the triggering of cytosolic phospholipase A2 (cPLA2) and arachidonic acid (AA) release. The heterotypic stimulation of FcγR induced the expression of COX‐2 in a time and dose‐dependent manner and activated the NF‐κB system as judged from the degradation of IκB‐α protein. In summary, the present data indicate that activation of the p42‐MAP / ERK pathway occurs after cross‐linking FcγRI and FcγRIIA receptors in monocytic cells; however, this is not coupled to the cPLA2 route, which leads to the release of AA. Noteworthy,heterotypic activation involving combined cross‐linking of both FcγRI and FcγRIIA has a robust effect on the oxidative metabolism of AA by a mechanism involving κB‐dependent trans‐activation of COX‐2.

Src Homology 2–Containing Inositol 5′-Phosphatase 1 Negatively Regulates IFN-γ Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12

“…initially characterized by Trotta et al (9,46) in NK cells. Similar findings implicating Erk in FcR-induced cytokine production were observed for monocytic cells following cross-linking of FcgRI or FcgRIIa (47). Thus, our studies lend support to the involvement of Erk in the regulation of cytokine production following FcR activation and provide a potential mechanism by which cytokines, such as IL-12, can enhance the FcgRIIIa-mediated effects within NK cells.…”

Activation of Monocytic Cells Through Fcγ Receptors Induces the Expression of Macrophage-Inflammatory Protein (MIP)-1α, MIP-1β, and RANTES

“…3). In keeping with previous studies addressing homotypic stimulation of Fc␥R, the responses were less robust, thus suggesting that cross-linking of Fc␥R by mAb does not produce strong Fc-Fc␥R interactions, such as those required for optimal activation of monocytes (26,27). Noteworthy, the pattern of induction elicited by other stimuli was somewhat different from that elicited by IC, albeit the induction of both MIP-1␣ and MIP-1␤ was again most prominent.…”

“…In fact, we have not detected the expression of GATA-1 mRNA by the RT-PCR approach in THP-1 cells (data not shown). In contrast, the functional relevance of the C/EBP␤ site in the transcriptional regulation of MIP-1␣ can be supported by several arguments: 1) the presence of a high homology C/EBP␤ site on the proximal promoter region according to rigorous criteria; 2) the appearance of binding activity to this site in the nuclear extracts displaying a strong dependency on critical bases in the core sequence, before the induction of MIP-1␣ expression; 3) the similar dose-response pattern of both MIP-1␣ expression and appearance of C/EBP␤-binding activity; 4) the parallel pattern of MAP kinase activation (26) and C/EBP␤-binding activity in the nuclear extracts elicited by Fc␥R cross-linking, which agrees with the reported phosphorylation at threonine-235 of C/EBP␤ by MAP kinase as an essential step for C/EBP␤ activation (43). Moreover, the pattern of MIP-1␣ induction in this system is similar to that disclosed for cyclooxygenase-2 (26), a gene the expression of which has been found to be strongly dependent on C/EBP␤ in both human and mouse macrophages (44,45).…”

“…These findings make the THP-1 cell line a suitable model for the study of monocytic cells, because it may grow without adhering to plastic and then circumvents the occurrence of adherence-mediated activation. Attempts to relate the expression of chemokines to the cross-linking of the specific types of Fc␥R expressed in THP-1 cells were conducted by the homotypic approach by incubating THP-1 cells with 10 g/ml mAb reacting with Fc␥RI, Fc␥RIIA, and Fc␥RIII for 10 min at 4°C, followed by washing to eliminate the Ab not bound to cell receptors and replacement by new medium prewarmed at 37°C before the addition of goat anti-mouse F(abЈ) 2 (26). The pattern of chemokine induction elicited by the mAb resembled one another, as well as that produced by the combination of mAb (Fig.…”

Inhibition of Interleukin-4-induced Class Switch Recombination by a Human Immunoglobulin Fcγ-Fcϵ Chimeric Protein

“…However, the role(s) of Fc␥RIIA versus -B in the effects of GE2 will require further dissection. It has been reported recently that the triggering of Fc␥RIIA activates ERK (26). If GE2 binds to and cross-links CD23 to Fc␥RIIA on the surface of B cells, this should lead to ERK activation and may be one likely pathway for the effect of GE2.…”