BIOCHEMICAL
MEDICINE
AND
METABOLIC
BIOLOGY
46,274-276
(191)
LETTER TO THE EDITOR Vasoactive Intestinal Peptide: A Chronoimmunomodulator? Recent studies documented that vasoactive intestinal peptide (VIP) interacts with immune cells as an immunosuppressive agent (1). Because circulating VIP (2) and T lymphocytes (3) fluctuate according to a circadian rhythm, this study was performed to detect a temporal relationship between the two variables along the 24-h span. The study was carried out on 10 clinically healthy subjects (5 males and 5 females, 20-25 years old) at the seventh day of a synchronizing protocol for lightdark regimen (light on, 0700; light off, 2300), meal timing (breakfast, 0800; lunch, 1230; dinner, 1830) and diet. Blood collection was performed at 0600,0800, 1200, 1800, 2000, and 2400 in subjects lying recumbent in bed from 8 h prior to the first blood sampling. Plasma VIP and lymphocyte typization were carried out according to methods described elsewhere (49. Time-qualified values were analyzed by the Cosinor method (6,7) in order to statistically validate the circadian rhythm and to quantify the rhythmometric properties. Figure 1 shows the circadian time-qualified mean values of VIP and total T (OKT3), T helper (OKT4), and T citotoxic/suppressor (OKTS) lymphocytes. The chronograms show a nyctohemeral variability. Table 1 displays the results by Cosinor analysis demonstrating that circulating VIP and T-lymphocyte subsets exhibit a statistically significant circadian rhythm (P < 0.05 for all investigated variables). Importantly, the acrophase timing is located early in the evening (at 1820) for VIP and during the night for all the lymphocyte subtypes. A t test validated that the temporal lag in acrophase between VIP and each T-cell subset is highly significant (P < 0.001 in all statistical comparisons). As the circadian variability in blood concentration of T cells is influenced by the inhibitory action of cortisol (8), so the temporal phase shift between VIPemia and T cell blood count may have a physiological meaning in modulating T-cell proliferation along the 24-h span, VIP exerting an immunosuppressive action. REFERENCES 1. Weigent DA, Carr DJJ, Blalock JE. Bidirectional communication between the neuroendocrine and immune systems. Ann N Y Acud Sci 57917-27, 1990. 2. Cugini P, Re M, Di Palma L, Leone G, Battisti P, Canova R, Gasbarrone L, Cianetti A. Vasoactive intestinal peptide fluctuates in human blood with a circadian rhythm. Submitted for publication. 3. Levi F, Reinberg A, Canon C. Clinical immunology and allergy. In Biological Rhythms in Clinical Practice (Arendt J, Minors DS, Waterhouse JM, Eds.). London: Wright, 1989, pp. 99-135. 274 0885-4505/91 $3.00 Copyright 8 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
LETTER
275
TO THE EDITOR
TIME
TIME
(clock
(clock
FIG. 1. (A) Total T lymphocytes; (B) helper/inducer lymphocytes.
hour)
hour)
T lymphocytes; (C) suppressor/cytotoxic
T
4. Fahrenkrug J. Vasoactive intestinal peptide: Measurement, distribution and function. Digestion 19149-169, 1979. 5. Signore A, Cugini P, Letizia C, Lucia P, Murano G, Pozzilli P. Study of the diurnal variation of human lymphocyte subsets. J Clin Lab Immun 1225-28, 1985. 6. Halberg F, Johnson EA, Nelson W, Runge W, Sothem RB. Autorhythmometry. Procedures for physiologic self-measurements and their analysis. Physiol Teacher lrl-11, 1972. 7. Halberg F, Tong YL, Johnson EA. Circadian system phase: An aspect of temporal morphology;
TABLE 1 Cosinor-Estimated Parameters of Circadian Rhythm for Plasma Cortisol (PC), Vasoactive Intestinal Peptide (VIP), Total T Lymphocytes (OKT3), T Helper Lymphocytes (OKT4), and T Suppressor/Cytotoxic Lymphocytes (OKT8) Variable
RDL
Mesor 2 SE
VIP
0.03
42.67
+ 1.70
OKT3
0.01
50.67
2 0.88
OKT4
0.02
32.93
+ 0.94
OKT8
0.02
22.00
k 0.90
Note. RDL: P value for rhythm detection level.
Amplitude (95% CL)
Acrophase (95% CL)
11.33 (1.30; 30.51) 3.82 (1.85; 10.13) 1.32 (0.29; 2.40) 1.33 (0.22; 2.56)
18.20 (08.12; 19.00) 03.04 (22.00; 07.00) 02.16 (23.08; 06.28) 03.00 (22.04; 06.12)
276
LElTER
TO THE EDITOR
procedures and illustrative examples. In The Cellular Aspects of Biorhythms (Von Mayersbach H, Ed.). New York: Springer-Verlag, 1967, pp. 20-48. 8. Kawate T, Abo T, Hinnma S, Kumagay K. Studies on the bioperiodicity of the immune response. II. Covariations of murine T and B cells and a role of corticosteroid. J Immunol u6:1364-1367, 1981.
P. CUGINI P. LUCIA
L. DI PALMA P. POZZILLI M. RE Institutes University
of II “La
Medical Clinics Sapienza”
end V Medical
Clinics
R. CANOVA L. GASBARRONE A. CIANETTI Department of Internal Medicine S. Camillo De Lellis Hospital Rome, Italy Received March 25. 1991
and Clinical
Research
Laboratory
MEDICINE
AND
METABOLIC
BIOLOGY
46,274-276
(191)
LETTER TO THE EDITOR Vasoactive Intestinal Peptide: A Chronoimmunomodulator? Recent studies documented that vasoactive intestinal peptide (VIP) interacts with immune cells as an immunosuppressive agent (1). Because circulating VIP (2) and T lymphocytes (3) fluctuate according to a circadian rhythm, this study was performed to detect a temporal relationship between the two variables along the 24-h span. The study was carried out on 10 clinically healthy subjects (5 males and 5 females, 20-25 years old) at the seventh day of a synchronizing protocol for lightdark regimen (light on, 0700; light off, 2300), meal timing (breakfast, 0800; lunch, 1230; dinner, 1830) and diet. Blood collection was performed at 0600,0800, 1200, 1800, 2000, and 2400 in subjects lying recumbent in bed from 8 h prior to the first blood sampling. Plasma VIP and lymphocyte typization were carried out according to methods described elsewhere (49. Time-qualified values were analyzed by the Cosinor method (6,7) in order to statistically validate the circadian rhythm and to quantify the rhythmometric properties. Figure 1 shows the circadian time-qualified mean values of VIP and total T (OKT3), T helper (OKT4), and T citotoxic/suppressor (OKTS) lymphocytes. The chronograms show a nyctohemeral variability. Table 1 displays the results by Cosinor analysis demonstrating that circulating VIP and T-lymphocyte subsets exhibit a statistically significant circadian rhythm (P < 0.05 for all investigated variables). Importantly, the acrophase timing is located early in the evening (at 1820) for VIP and during the night for all the lymphocyte subtypes. A t test validated that the temporal lag in acrophase between VIP and each T-cell subset is highly significant (P < 0.001 in all statistical comparisons). As the circadian variability in blood concentration of T cells is influenced by the inhibitory action of cortisol (8), so the temporal phase shift between VIPemia and T cell blood count may have a physiological meaning in modulating T-cell proliferation along the 24-h span, VIP exerting an immunosuppressive action. REFERENCES 1. Weigent DA, Carr DJJ, Blalock JE. Bidirectional communication between the neuroendocrine and immune systems. Ann N Y Acud Sci 57917-27, 1990. 2. Cugini P, Re M, Di Palma L, Leone G, Battisti P, Canova R, Gasbarrone L, Cianetti A. Vasoactive intestinal peptide fluctuates in human blood with a circadian rhythm. Submitted for publication. 3. Levi F, Reinberg A, Canon C. Clinical immunology and allergy. In Biological Rhythms in Clinical Practice (Arendt J, Minors DS, Waterhouse JM, Eds.). London: Wright, 1989, pp. 99-135. 274 0885-4505/91 $3.00 Copyright 8 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
LETTER
275
TO THE EDITOR
TIME
TIME
(clock
(clock
FIG. 1. (A) Total T lymphocytes; (B) helper/inducer lymphocytes.
hour)
hour)
T lymphocytes; (C) suppressor/cytotoxic
T
4. Fahrenkrug J. Vasoactive intestinal peptide: Measurement, distribution and function. Digestion 19149-169, 1979. 5. Signore A, Cugini P, Letizia C, Lucia P, Murano G, Pozzilli P. Study of the diurnal variation of human lymphocyte subsets. J Clin Lab Immun 1225-28, 1985. 6. Halberg F, Johnson EA, Nelson W, Runge W, Sothem RB. Autorhythmometry. Procedures for physiologic self-measurements and their analysis. Physiol Teacher lrl-11, 1972. 7. Halberg F, Tong YL, Johnson EA. Circadian system phase: An aspect of temporal morphology;
TABLE 1 Cosinor-Estimated Parameters of Circadian Rhythm for Plasma Cortisol (PC), Vasoactive Intestinal Peptide (VIP), Total T Lymphocytes (OKT3), T Helper Lymphocytes (OKT4), and T Suppressor/Cytotoxic Lymphocytes (OKT8) Variable
RDL
Mesor 2 SE
VIP
0.03
42.67
+ 1.70
OKT3
0.01
50.67
2 0.88
OKT4
0.02
32.93
+ 0.94
OKT8
0.02
22.00
k 0.90
Note. RDL: P value for rhythm detection level.
Amplitude (95% CL)
Acrophase (95% CL)
11.33 (1.30; 30.51) 3.82 (1.85; 10.13) 1.32 (0.29; 2.40) 1.33 (0.22; 2.56)
18.20 (08.12; 19.00) 03.04 (22.00; 07.00) 02.16 (23.08; 06.28) 03.00 (22.04; 06.12)
276
LElTER
TO THE EDITOR
procedures and illustrative examples. In The Cellular Aspects of Biorhythms (Von Mayersbach H, Ed.). New York: Springer-Verlag, 1967, pp. 20-48. 8. Kawate T, Abo T, Hinnma S, Kumagay K. Studies on the bioperiodicity of the immune response. II. Covariations of murine T and B cells and a role of corticosteroid. J Immunol u6:1364-1367, 1981.
P. CUGINI P. LUCIA
L. DI PALMA P. POZZILLI M. RE Institutes University
of II “La
Medical Clinics Sapienza”
end V Medical
Clinics
R. CANOVA L. GASBARRONE A. CIANETTI Department of Internal Medicine S. Camillo De Lellis Hospital Rome, Italy Received March 25. 1991
and Clinical
Research
Laboratory
