Role of proinflammatory cytokines in controlling lymphocyte trafficking during fever-range thermal stress
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The evolutionarily conserved fever response is the least understood component of the acute phase reaction to infection. A primary mechanism of action attributed to fever is that it promotes lymphocyte delivery to organs through hemodynamic parameters such as vasodilation and blood flow. Recent studies in our laboratory have shown that temperatures in the range of physiological fever proactively regulate adhesion events in lymphocytes and vascular endothelium, thus improving lymphocyte trafficking to selected tissue sites. The present study investigated the molecular mechanisms underlying thermal stimulation of lymphocyte-endothelial adhesion and lymphocyte trafficking. This issue was addressed in 3 distinct vascular sites: (1) high endothelial venules (HEV) of secondary lymphoid organs, which are portals for efficient recirculation of naïve and central memory T lymphocytes; (2) resting endothelium of normal tissues that mediate relatively low basal levels of trafficking; and (3) tumor vessels that are inefficient in supporting lymphocyte extravasation because of low expression of trafficking molecules. Fever-range thermal stress was shown to act in a highly site-specific manner to regulate multiple steps in the adhesion cascade required for migration of blood-borne lymphocytes across vascular endothelial barriers. Heat treatment improved homeostatic recirculation across gate-keeper HEV by dually regulating adhesion in both lymphocytes and cuboidal endothelial cells lining HEV. In lymphocytes, fever-range thermal stress increased the binding activity of the L-selectin homing receptor, thereby augmenting lymphocyte tethering and rolling along HEV under shear. In HEV, thermal stress enhanced intravascular display of CCL21 chemokine and intercellular adhesion molecule-1 (ICAM-1), which led to ∼ a 2-fold increase in firm adhesion and extravasation of naïve and central memory T cells into secondary lymphoid organs. In sharp contrast, fever range thermal stress failed to increase ICAM-1 expression or homing of blood-borne lymphocytes across non-activated squamous endothelium of normal tissues. However, a substantial increase in trafficking of CD8 + T cells across tumor vessels was detected in response to fever-range thermal therapy. This acute response was associated with increased intravascular expression of ICAM-1 on tumor vessels. A unifying feature was the identification of the inflammatory cytokine, interleukin-6 (IL-6), as the key integrator of thermally induced L-selectin adhesion in lymphocytes and ICAM-1 expression on vascular endothelial cells. Taken together, these studies indicate that the thermal component of physiologic fever acts systemically as an alert system to enhance the level of homeostatic trafficking across the HEV-axis during inflammation. These findings also raise the possibility that clinical thermal therapy can capitalize on the proadhesive mechanism of action of fever to augment delivery of tumor specific CDT8 + effector cells to the tumor microenvironment.