n-butyrate downregulates the stimulatory function of peripheral blood-derived antigen-presenting cells: a potential mechanism for modulating T-cell responses by short-chain fatty acids.
Modulation of proliferative T-cell responses by n-butyrate has been suggested to result from direct interference with cell cycle progression. Considering the important role of antigen-presenting cells (APC) in T-cell activation, we were particularly interested in studying the impact of n-butyrate on these cells. We demonstrated that pretreatment of human peripheral blood mononuclear cells (PBMC) or monocytes with this agent resulted in a dose- and time-dependent downregulation of their capability to stimulate T-cell responses with a similar pattern of inhibition when this agent was present throughout the culture period. Pretreatment with n-butyrate was effective in preventing both alloresponses and T-cell proliferation to immobilized anti-CD3 monoclonal antibody (mAb) suggesting alteration of costimulatory function. Flow cytometric analysis revealed that interferon-gamma (IFN-gamma)-induced upregulation of B7-1 expression on monocytes was profoundly inhibited by n-butyrate. Furthermore, this agent significantly suppressed the expression of intercellular adhesion molecule-1 (ICAM-1) or lymphocyte function-associated antigen-3 (LFA-3). In contrast, constitutive as well as cytokine-induced expression of B7-2 was enhanced by n-butyrate. Additionally, in monocytes, but not in T cells, treatment with n-butyrate led to significant alteration of membrane integrity owing to apoptotic cell death. Our findings indicate that modulation of T-cell responses by n-butyrate could also result from altered APC function, possibly as a consequence of downregulating distinct adhesion and/or costimulatory receptors as well as of inducing apoptosis. A potential clinical relevance of short-chain fatty acids for reducing T-cell-mediated immune reactions via modulating APC function is speculated.
Böhmig
G A
GA
Institute of Immunology, University of Vienna, Austria.
Krieger
P M
PM
Säemann
M D
MD
Wenhardt
C
C
Pohanka
E
E
Zlabinger
G J
GJ
D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D018929:Cell Culture Techniques; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
D000954:Antigens, Surface; D002087:Butyrates; D020148:Butyric Acid