The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta.

Abstract

Wallerian degeneration (WD) is the inflammatory response of the nervous system to axonal injury, primarily attributable to the production of cytokines, the mediator molecules of inflammation. We presently document the involvement of the inflammatory cytokines TNFalpha, interleukin (IL)-1alpha, and IL-1beta in peripheral nerve (PNS) injury in C57/BL/6NHSD (C57/BL) mice that display the normal rapid progression of WD (rapid-WD) and C57/BL/6-WLD/OLA/NHSD mice that display abnormal slow progression of WD (slow-WD). TNFalpha and IL-1alpha mRNAs were expressed, whereas TNFalpha but not IL-1alpha protein was synthesized in intact PNS of C57/BL mice. TNFalpha and IL-1alpha protein synthesis and secretion were rapidly upregulated during rapid-WD in Schwann cells. IL-1beta mRNA expression and protein synthesis and secretion were induced sequentially in Schwann cells with a delay after injury. Thereafter, recruited macrophages contributed to the production of TNFalpha, IL-1alpha, and IL-1beta, which in turn augmented myelin phagocytosis by macrophages. Observations suggest that TNFalpha and IL-1alpha are the first cytokines with protein production that is upregulated during rapid-WD. TNFalpha and IL-1alpha may initiate, therefore, molecular and cellular events in rapid-WD (e.g., the production of additional cytokines and NGF). TNFalpha, IL-1alpha, and IL-1beta may further regulate, indirectly, macrophage recruitment, myelin removal, regeneration, and neuropathic pain. In contrast to rapid-WD, the production of TNFalpha, IL-1alpha, and IL-1beta protein was deficient in slow-WD, although their mRNAs were expressed. mRNA expression and protein production of TNFalpha, IL-1alpha, and IL-1beta were differentially regulated during rapid-WD and slow-WD, suggesting that mRNA expression, by itself, is no indication of the functional involvement of cytokines in WD.