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Neuritogenic Effects of T Cell-Derived IL-3 on Mouse Splenic Sympathetic Neurons In Vivo¹

Yukiko Kannan-Hayashi^2,*,,||, Kensaku Okamura^*, Shizuka Hattori^*, Mitsuru Kuwamura, Etsuko Higuchi^*, Hiroki Terayama^*, Mitsuaki Moriyama^*, Masafumi Mukamoto, Masaji Okada, Yoshiyuki Ohsugi^¶ and Yoichi Nakamura^*

^* Laboratory of Integrative Physiology, Laboratory of Veterinary Pathology, and Laboratory of Veterinary Epidemiology, Division of Veterinary Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan; Clinical Research Center, National Kinki-Chuo Hospital for Chest Diseases, Sakai, Osaka, Japan; ^¶ MRA Unit, Chugai Pharmaceutical, Chuo-ku, Tokyo, Japan; and ^|| Department of Human Life Science, Baika Junior College, Shukunosho, Ibaraki, Osaka, Japan

To determine the role played by lymphocytes and cytokines in the growth of sympathetic neurons in vivo, the innervation and cytokine levels were examined in the spleens of SCID mice that lack T and B cells. Splenic noradrenaline, nerve growth factor (NGF), and IL-1β levels were elevated in SCID mice. Immunohistochemical examination revealed that the density of tyrosine hydroxylase-positive (TH⁺) fibers of splenic central arteries in SCID mice was increased compared with wild-type C.B-17 mice, while SCID mice had significantly fewer TH⁺ fibers in their periarteriolar lymphatic sheaths (PALS). Two weeks after SCID mice were injected with C.B-17 splenic T cells, their TH⁺ fiber staining increased in the PALS. IL-3 levels increased significantly in SCID mice following T cell reconstitution, and the administration of anti-IL-3 Ab blocked the above T cell-induced increase in innervation in the PALS. Anti-IL-3 treatment also inhibited the regeneration of splenic sympathetic neurons in C.B-17 mice after they were chemically sympathetomized with 6-hydroxydopamine. Depletion of NK cells by anti-asialo GM1 promoted the splenic innervation in SCID mice, while there were no significant changes in the innervation between CD8⁺ T cell-deficient β₂-microglobulin knockout mice and their wild type. Our results suggest that T cells (probably CD4⁺ Th cells but not CD8⁺ CTLs) play a role in regulating the sympathetic innervation of the spleen; this effect appeared to be mediated, at least in part, by IL-3. On the contrary, NK cells may exert an inhibitory effect on the sympathetic innervation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid for Scientific Research C (15580263) from the Ministry of Education, Science, Sports, and Culture of Japan.

² Address correspondence and reprint requests to Dr. Yukiko Kannan-Hayashi, Department of Human Life Science, Baika Junior College, 2-19-5, Shukunosho, Ibaraki, Osaka, 567-8578, Japan. E-mail address: y-hayashi{at}baika.ac.jp

³ Abbreviations used in this paper: NGF, nerve growth factor; PALS, periarteriolar lymphatic sheath; TH, tyrosine hydroxylase; β₂m KO, β₂-microglobulin knockout; RT, room temperature; 6-OHDA, 6-hydroxydopamine.