Interleukin-4 blocks proliferation of retinal progenitor cells and increases rod photoreceptor differentiation through distinct signaling pathways.
Interleukin-4 (IL-4), an anti-inflammatory cytokine, has been related to the differentiation of the rodent retina in vitro, but constitutive presence of either IL-4 or of IL-4 receptor in the retina has not been reported. In this work we examined the expression of IL-4 and its specific receptor alpha subunit (IL-4Ralpha). IL-4Ralpha is expressed both in neural retina and non-neural ocular tissue, while IL-4 was found mainly in non-neural tissue. We characterized a novel trophic effect of IL-4 upon the retina. We showed that IL-4 can inhibit the proliferation of retinal cells (approximately 40%) through the cAMP-PKA pathway and associated with a reduction of cyclin D1 and increase of p27(kip1). IL-4 also promotes the differentiation of rod photoreceptors. Activation of tyrosine kinases, protein kinase C, and mitogen-activated kinases of the Erk family were required for IL-4-induced rod photoreceptor differentiation, independent of the release of other trophic factors in culture. Taken together, our results show, for the first time, that IL-4 directly modulates proliferation of retinal cells and rod photoreceptor differentiation, through distinct signaling pathways.
da Silva
Ana Gabriela Ledo Santos
AG
Programa de Neurobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bl G, Cidade Universitária, 21949-900, Rio de Janeiro, RJ, Brazil.
Campello-Costa
Paula
P
Linden
Rafael
R
Sholl-Franco
Alfred
A
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011494:Protein Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000187:drug effects; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects*; D012243:Rhodopsin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D053662:Interleukin-4 Receptor alpha Subunit
D015703:Antigens, CD; D000242:Cyclic AMP; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D015847:Interleukin-4; D011494:Protein Kinases; D011956:Receptors, Cell Surface; D012243:Rhodopsin; D013936:Thymidine; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit