RAC1/P38 MAPK Signaling Pathway Controls β1 Integrin–Induced Interleukin-8 Production in Human Natural Killer Cells

Abstract

The MAP kinase (MAPK) p38 plays a key role in regulating inflammatory responses. Here, we demonstrate that beta1 integrin ligation on human NK cells results in the activation of the p38 MAPK signaling pathway, which is required for integrin-triggered IL-8 production. In addition, we identified some of the upstream events accompanying the beta1 integrin-mediated p38 MAPK activation, namely, the activation of the Rac guanine nucleotide exchange factor (GEF) p95 Vav, the small G protein Rac1, and the cytoplasmic kinases Pak1 and MKK3. Finally, we provide direct evidence that p95 Vav and Rac control the activation of p38 MAPK triggered by beta1 integrins.

p38 MAPK is a critical regulator of the constitutive and the β4 integrin‐regulated expression of IL‐6 in human normal thymic epithelial cells

“…Under these conditions, we found that g 4 stimulation intensely increased the low levels of activation of p38, ERK, Rac1, PAK1 and MKK3/ MKK6 found in unstimulated cells. It has been reported that Rac1 controls ERK, Jnk, and p38 activation, that PAK1 is involved in ERK and p38 activation, and that MKK3/MKK6 lie upstream the activation of p38 [25][26][27][28]. No data were available before our report on activation of p38 signaling pathway following g 4 integrin stimulation.…”

“…If indicated, before stimulation TEC (2.5×10 5 /ml) were treated with antisense and complementary sense ODN (100 ? g/ml) in culture medium for 56 h [28].…”

Insulin-like Growth Factor-binding Protein-5 (IGFBP-5) Stimulates Growth and IGF-I Secretion in Human Intestinal Smooth Muscle by Ras-dependent Activation of p38 MAP Kinase and Erk1/2 Pathways

“…In COS-7 and HeLa cells, the small GTPases Rac, Rho, and Cdc42 are requisite cofactors in Ras-dependent Raf activation and subsequent activation of Erk1/2 (33)(34)(35). These monomeric G-proteins have also been shown to play a role in the activation of MKK3/6 leading to p38 MAP kinase activation (36,37). It remains to be determined whether IGFBP-5-induced growth mediated by the Raf-Erk1/2 or p38 MAP kinase pathways involves the participation of the GTPases Rho, Rac, and Cdc42.…”

IgE-Mediated Activation of NK Cells Through FcγRIII

“…In our study, stimulation of Fc␥RIII with IgE was always weaker than with IgG for both cytokine production and ADCC. The cytokine production by NK cells upon IgE stimulation despite very low affinity of IgE binding to Fc␥RIII may be mediated by cooperation of specific adhesion molecules because adhesion molecules have been shown to be involved in cytokine production and cytotoxicity by NK cells (21,22). An obvious question may occur whether IgE-mediated NK activation takes place under physiological conditions with such low affinity of IgE to Fc␥RIII and requirement of higher concentration of IgE than IgG.…”