Modulation of T-cell signalling by non-esterified fatty acids.

Polyunsaturated fatty acids (PUFAs) have been shown to be immunosuppressive. In particular, they can decrease important T-cell functions that may have a profound impact on the acquired immune response. Several mechanisms may explain the immunosuppressive properties of PUFAs. Here we review the mechanisms by which they interfere with T-cell activation. PUFAs affect lipid rafts composition and function that play an essential role in T-cell signalling. The possible physiological and pathological significances of this immunomodulation by PUFAs are discussed. Further mechanistic studies and randomized controlled clinical trials are needed to assess more accurately their effects in healthy and pathological states.

Acute in vivo elevation of intravascular triacylglycerol lipolysis impairs peripheral T cell activation in humans.

BACKGROUND: Previous studies have shown suppressive effects of polyunsaturated fatty acids (PUFAs) on T cell proliferation, but the precise mechanism for this effect has not been fully investigated in vivo in humans. OBJECTIVE: The objective was to determine whether this effect is the result of altered T cell membrane properties and impaired CD3- and CD28-mediated signaling in vivo in humans. DESIGN: Peripheral T cells were isolated from healthy subjects before and 2 h after an intravenous infusion of heparin plus a PUFA-rich lipid emulsion during a euglycemic hyperinsulinemic clamp to induce a 2.5-fold elevation in plasma linoleic acid concentration without significant change in plasma total free fatty acid concentrations. RESULTS: Intravenous infusion of heparin plus the lipid emulsion reduced peripheral T cell membrane fluidity and altered lipid raft organization, both of which were associated with reduced T cell proliferation after stimulation with CD3 plus CD28. Tyrosine phosphorylation of linker of activated T cells and activation of protein kinase B in T cells were also impaired without a reduction in T cell receptor expression. In addition, acute PUFA elevation was associated with a reduction in T cell membrane cholesterol exchange with the cellular milieu ex vivo. CONCLUSIONS: A selective increase in plasma linoleic acid concentration and in intravascular lipolysis has a suppressive effect on peripheral T cell CD28-dependent activation, and this effect is associated with changes in plasma membrane properties. Our results have important implications for nutritional therapy in patients at high risk of septic complications and may also be of relevance to postprandial lipid metabolism disorders such as insulin resistance and type 2 diabetes.

Differentiation state-selective roles of p38 isoforms in human intestinal epithelial cell anoikis.

BACKGROUND & AIMS: Little is known of the signaling events implicated in the induction of human enterocytic anoikis. In the present study, we analyzed the role of the stress-activated protein kinase p38 in this process. METHODS: Anoikis was induced in undifferentiated and differentiated enterocytes by inhibition of focal adhesion kinase (Fak; pharmacologic inhibition or overexpression of a dominant negative form) or beta1 integrins (antibody blocking), or by maintaining cells in suspension. Expression/activation parameters of p38 (isoforms alpha, beta, gamma, delta) and of the Fak/phosphatidylinositol-3-kinase (PI3-K)/Akt anoikis-suppressing pathways were analyzed. Kinase activities of p38 isoforms also were blocked by pharmacologic inhibitors or by overexpression of dominant-negative forms. RESULTS: (1) p38 activation is sustained transiently after induction of anoikis in both undifferentiated and differentiated enterocytes; (2) such sustenance of p38 activation is associated with a down-regulation of the Fak/PI3-K/Akt pathway; (3) distinct profiles of p38 isoform expression are exhibited by undifferentiated (alpha, beta, gamma) and differentiated (alpha, gamma, delta) enterocytes; (4) none of the 4 known p38 isoforms was found to promote cell survival in either differentiation state; and (5) only p38beta and p38delta are required specifically for anoikis in undifferentiated and differentiated cells, respectively. CONCLUSIONS: Distinct p38 isoforms play a major role in the induction of enterocytic anoikis and the regulation of such selective p38 isoform-mediated anoikis is linked with the state of cell differentiation. These data provide novel insights into the synchronized regulation of cell survival/death required in the epithelial renewal process along the human intestinal crypt-villus axis.