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Review
. 2007 Jul;39(1):84-96.
doi: 10.1016/j.cyto.2007.07.184.

Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance

Trupti D Vardam  1 , Lei Zhou, Michelle M Appenheimer, Qing Chen, Wang-Chao Wang, Heinz Baumann, Sharon S Evans
Affiliations
Review

Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance

Trupti D Vardam et al. Cytokine. 2007 Jul.

Abstract

The pleiotropic cytokine, interleukin-6 (IL-6), has emerged in recent years as a key regulator of the transition from innate to adaptive immunity through its ability to modulate leukocyte recruitment at inflammatory sites. This review highlights a newly identified role for IL-6 trans-signaling, initiated by an agonistic complex of IL-6 and a soluble form of IL-6 receptor alpha, in heightening immune surveillance of peripheral lymphoid organs during febrile inflammatory responses. Inflammatory cues provided by the thermal component of fever trigger IL-6 trans-signaling to act at discrete levels in the multistep adhesion cascade that governs the entry of blood-borne lymphocytes across 'gatekeeper' high endothelial venules (HEVs) in lymph nodes and Peyer patches. IL-6 trans-signaling-dependent mechanisms have been elucidated during thermal stimulation of primary tethering and rolling of lymphocytes along the lumenal surface of HEVs as well as during secondary firm arrest of lymphocytes in HEVs prior to their migration into the underlying parenchyma. These mechanisms profoundly increase the probability that lymphocytes that continuously patrol the body will engage in productive encounters with target antigens sequestered within lymphoid organs. Findings that the lymphocyte-HEV-IL-6 trans-signaling biological axis functions as a thermally-sensitive alert system that promotes immune surveillance provide insight into one of the unresolved mysteries in immunology regarding the benefits of mounting a febrile reaction during inflammation.

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Figures

Figure 1
Figure 1. Role of IL-6 in promoting lymphocyte trafficking in acute and chronic inflammation
IL-6 transduces signals via membrane-anchored gp130 molecules through a classical pathway initiated by binding to membrane-anchored IL-6Rα (mIL-6Rα) or by a transsignaling mechanism in which IL-6 associates with a soluble form of IL-6Rα (sIL-6Rα). IL-6/IL-6Rα then recruits gp130 into hexameric complexes that initiate activation of the downstream signaling molecules STAT3 and ERK-1/2. IL-6 is causal in increasing the adhesive potential of both lymphocytes and vascular endothelial cells, which leads to enhanced trafficking of lymphocytes to lymphoid organs as well as to sites of acute and chronic inflammation.
Figure 2
Figure 2. Thermal stimulation of primary adhesion is dependent on IL-6 trans-signaling
BALB/c mice were maintained at normal body temperature (NT) or treated for 6 hours with whole-body fever-range hyperthermia (WBH, 39.5°C ± 0.5°C). In selected experiments, mice were injected i.v. with function blocking IL-6 monoclonal antibody or with recombinant soluble gp130 (sgp130) prior to thermal treatment. Isolated splenocytes from experimental mice were analyzed for L-selectin–dependent primary adhesion to mouse PLN HEVs in a frozen-section adherence assay as described previously [41, 118, 151]. Photomicrographs show darkly stained exogenous splenocytes bound to HEVs which are below the plane of focus (indicated by arrows). Note that antibody blockade and soluble gp130 markedly reduced the number of WBH-treated lymphocytes adhering to individual HEVs. Bar = 50 μm.
Figure 3
Figure 3. Thermal induction of ICAM-1 on HEVs is dependent on IL-6
WT or IL-6–deficient (Il6−/−) mice (C57BL/6 background) were exposed to fever-range thermal stress (39.5 ± 0.5°C) for 6 hours and the intravascular density of ICAM-1 on HEVs of peripheral lymph nodes was assessed by immunofluorescence staining as described [40]. The position of near-cuboidal HEVs in tissue sections is demarked by counter-staining for the HEV-restricted molecule, PNAd. Thermal stress strongly upregulates ICAM-1 density on PNAd+ HEVs in WT but not in Il6−/− mice. Bar = 50 μm.
Figure 4
Figure 4. Cytokine-mediated signal transduction and ICAM-1 induction in endothelial cells in vitro
Human derma microvascular endothelial cells (HMVEC) were treated with recombinant cytokines or with conditioned medium from LPS-treated monocytes (CM MΦ) for the indicated time periods. Equal amounts of cell extracts were analyzed by Western blotting for (A) signal transduction molecules, or (B) ICAM-1 expression.
Figure 5
Figure 5. IL-6 trans-signaling targets each step of adhesion cascade controlling leukocyte extravasation during acute and chronic inflammation
Thermally responsive trafficking molecules are shown in red. All trafficking molecules shown are regulated through an IL-6 trans-signaling mechanism with the exception of CCL21 (*) which is induced by febrile temperatures through an IL-6–independent mechanism.
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