Activation of Th lymphocytes alters pattern expression and cellular location of VIP receptors in healthy donors and early arthritis patients

Vasoactive Intestinal Peptide (VIP) is an important immunomodulator of CD4(+) cells in normal and pathological conditions, which exerts its anti-inflammatory and immunomodulatory actions through VPAC receptors, VPAC(1) and VPAC(2). Only a decrease in the expression of VPAC(1) mRNA on Th cells upon activation has been reported. Thus, the deepening in the knowledge of the behavior of these receptors may contribute to the design of new therapies based on their activation and/or blockade. In this study, we describe the expression pattern, cellular location and functional role of VIP receptors during the activation of human Th cells in healthy conditions and in early arthritis (EA). The protein expression pattern of VPAC(1) did not change with the activation of Th lymphocytes, whereas VPAC(2) was up-regulated. In resting cells, VPAC(1) was located on the plasma membrane and nucleus, whereas it only appeared in the nucleus in activated cells. VPAC(2) was always found in plasma membrane location. VIP receptors signaled through a PKA-dependent pathway in both conditions, and also by a PKA-independent pathway in activated cells. Both receptors exhibit a potent immunomodulatory capacity by controlling the pathogenic profile and the activation markers of Th cells. These results highlight a novel translational view in inflammatory/autoimmune diseases.