Keep up the heat on IL-1

In this issue of Blood, Capitano et al report an unexpected but clinically relevant finding that mild heating of mice enhances the postradiation recovery of neutrophils via an IL-1, IL-17, and G-CSF mechanism.¹ 

Interleukin-1 is a master cytokine regulating inflammatory and immune responses. But there are two faces to the biology of IL-1: IL-1 can be causative in the manifestations of a broad spectrum of diseases,²  but IL-1 can also provide the host with protective mechanisms required to fight infection. For example, IL-1 stimulates hematopoiesis, particularly for neutrophils. Indeed, IL-1 was given to patients to shorten the nadir of bone-marrow suppression after chemotherapy.³  New data suggest that this latter property of IL-1 is enhanced at elevated temperatures during in vivo mouse models of neutrophil recovery from radiation.¹  This observation is consistent with what we know about IL-1.

Early research on IL-1 was carried out to isolate the endogenous fever–producing protein then called leukocytic pyrogen (reviewed in Dinarello⁴ ). Indeed, recombinant IL-1 (either IL-1α or IL-1β) is the most potent pyrogen for humans, producing fever at doses as low as 1 ng/kg (reviewed in Dinarello⁵ ). Human responses to IL-1 also target the hematopoietic system as IL-1 induces neutrophilia via induction of G-CSF. In fact, fever and neutrophilia are the two most consistent clinical findings in patients with autoinflammatory diseases; on IL-1 blocking monotherapy, both are promptly brought under control.²  Therefore, during infections, elevated body temperature (fever) may affect immunologic responses to the infectious agent. Several reports showed that immunologically active cytokines such as IL-2 result in greater in vitro responses at 39°C compared with 37°C.⁶ 

If elevated temperature augments immune responses, some asked whether elevated body temperature would affect the hematopoietic system. Capitano and coworkers have identified a unique mechanism that allows for a more rapid return of peripheral neutrophil after total body radiation. They demonstrate that mild elevation in body temperature (39.5°C) in mice that had been subjected to total body irradiation did in fact increase the recovery from neutropenia secondary to the radiation.¹  Hematopoietic stem cells and neutrophil progenitors were elevated by a mild increase in temperature and these increases were reflected in the total circulating neutrophils regardless of mouse strain. Most interestingly, these increases are apparently due to a cascade of cytokines in that IL-1 induces IL-17 and IL-17 induces G-CSF.

Consistently, total body radiation itself and elevated temperature alone did not result in any significant change in hematopoiesis; rather, the combination of total body radiation plus mild heat were required for the recovery from the neutropenia. Also consistently, the responses of cytokine to total body irradiation plus mild heating were observed primarily in the intestinal tissues. Blocking IL-1 receptors with the IL-1 receptor antagonist (IL-1Ra) was used to show that IL-17 responses to radiation and heat were IL-1–dependent. However, neutralization of IL-1β was not as effective as receptor blockade with IL-1Ra, and therefore a role for IL-1α is likely.

Regardless of the level of temperature, IL-17 dependence on IL-1 is known and similarly G-CSF is IL-17 dependent, as Capitano and colleagues demonstrate in their study. But why would the addition of mild heat to total body radiation be so effective in augmenting IL-1–driven IL-17 in the intestinal tissues? IL-1α is constitutively present as a precursor in intestinal epithelial cells from healthy humans and healthy mice. During total body radiation, intestinal epithelial cells die and release the IL-1α precursor, which is biologically active. Capitano et al raised the core temperature of mice by placing them in a warmer environment, which resulted in elevated core of 39.5°C for 6 hours. During that time and in that temperature range, two events could explain the enhanced production of IL-17: (1) IL-1α is more active at elevated temperature as was shown for lymphocytes and/or (2) at the standard (cooler) room temperature in which mice are housed, stress hormones such as glucocorticoids are produced and hold the production of IL-17 at bay. This raises the question of whether housing mice consistently at their thermoneutral temperature (30-31°C) instead of the cooler temperature normally used to house mice (∼ 22°C) could impact IL-1's function. This possibility is supported by the by the observation that IL-1 produces hypothermia in mice injected at laboratory ambient temperatures of 20 to 22°C, but it produces fever when placed in their thermoneutral zone.⁷ 

Clinically, these findings may apply to humans in terms of recovery of suppressed bone marrow during cancer therapy. This study has broad implications for the treatment of the paraneoplastic syndromes that include fever. Nevertheless, it brings new interest and data into the field to deal with the seemingly endless question of whether we treat fever in cancer or fall back to a lesson from evolution: elevated temperature (fever) is beneficial for host survival in fish and lizards⁸  and IL-1's property as a pyrogen predates it role in immune responses. The beneficial effect of mild elevation in core temperature on hematopoiesis was unexpected but should advance to therapeutic opportunities involving thermal therapy for patients in need of accelerated marrow production of neutrophils.