Brain, Behavior, and Immunity 15, 54–64 (2001) doi:10.1006/brbi.2000.0583, available online at http://www.idealibrary.com on Stress-Induced Changes in Peripheral Natural Killer Cell Cytotoxicity in Pigs May Not Depend on Plasma Cortisol Danuta Wrona, 1 Weronika Trojniar, Andrzej Borman, Ziemowit Ciepielewski, and Juliusz Tokarski Department of Animal Physiology, University of Gdan ´sk, ul. Kladki 24, 80-822 Gdan ´sk, Poland The study examined cortisol (COR) involvement in stress-related changes in natural killer cell cytotoxicity (NKCC). The relationship between blood COR level, phasic changes in NKCC, and the number of large granular lymphocytes (LGL) was examined in pigs during the course of 4-h immobilization stress (IMB) and for 6 days after its termination. NKCC was determined using 18-h 51 Cr-release assay, LGL number was assessed with a standard hematological method, and plasma COR level was measured by radioimmunoas- say. The blood level of COR was increasing during IMB (max 446∆% at the second hour) and decreased after its termination (max -59∆% on day 2). Changes in NKCC level and LGL number were biphasic; i.e., an initial increase in both measures (NKCC max 24∆%, LGL max 18∆%) in an early phase of stress (0–1h) was followed by their subsequent decrease (NKCC max -35∆%, LGL max -41∆%) in the late phase (3–4 h) of stress, which persisted for several days after termination of IMB. Thus, in the early phase of stress, there was a positive correlation between NKCC, LGL number, and COR levels (all elevated); a positive correlation between the measures also occurred after termination of IMB (all decreased). A negative correlation between COR and NKCC, which might be indicative of COR-related immunosuppression, was found only in the late (3–4 h) phase of stress. It is concluded that COR may be only one of multiple factors (possibly antagonistic) determining an actual immune response during stress.  2001 Academic Press Key Words: cortisol; immobilization stress; LGL; NK cytotoxicity; pigs. INTRODUCTION Much of the influence of the brain on immune events is exerted through the hypo- thalamic–pituitary–adrenal (HPA) axis. Activation of HPA axis by stressful stimuli including immobilization (IMB) results in adrenocortical secretion of cortisol (COR) in humans and nonhuman primates and corticosterone in mice and rats. COR is com- monly regarded as a leading agent responsible for the immunosuppressive effects of stress (Callewaert, Moudgil, Radcliff, & Waite, 1991; McEwen, Biron, Brunson, Bulloch, Chambers, Dhabhar, Goldfarb, Kitson, Miller, Spencer, & Weiss, 1997). In numerous studies, it was shown that the number and cytotoxic activity of natural killer (NK) cells with characteristic large granular lymphocyte (LGL) morphology (Herberman, 1982; Timonen, Reynolds, Ortaldo, & Herberman, 1982) are diminished by elevated concentrations of circulating COR (for review see Munck & Guyre, 1991). The hypothesis of a causal relationship between stress-induced immunosuppres- sion and the intensity of COR secretion has been recently challenged. Irwin (1994) associated immunosuppressive effects of stress with activity of CRH independent of the HPA axis and COR. Besides, unequivocal immunosuppressive effects of acute stress also seem doubtful. We (Tokarski, Wrona, Piskorzyn ´ ska, Borman, Witkowski, 1 To whom correspondence should be addressed. E-mail: wronada@biotech.univ.gda.pl. 54 0889-1591/01 $35.00 Copyright  2001 by Academic Press All rights of reproduction in any form reserved.