Second, exposure to cold can induce an ischemia-reperfusion-like state in the skin and peripheral tissue. A study into the effects of cryotherapy showed that local cooling of the skin decreases local tissue perfusion. The combination of tissue hypoperfusion and reperfusion upon the reactive vasodilatation that follows after rewarming is a form of ischemia/reperfusion (I/R). The potency of I/R to protect tissue against ischemic damage is known as Ischemic Preconditioning (IPC). It has the potential to influence the immune response through several pathways. For instance, recent animal work has shown that I/R results in downregulation of pro-inflammatory cytokines such as TNF-α and IL-6 and upregulation of anti-inflammatory cytokines such as IL-10. Furthermore, hypoxia-inducible factor (HIF) has been shown to be a major contributor to the I/R-induced IL-10 response.