Interleukin-1 alpha upregulates tumor necrosis factor receptors expressed by a human bone marrow stromal cell strain: implications for cytokine redundancy and synergy

Abstract

To explore the biochemical and physiologic basis of the overlapping effects of interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF-alpha) on myeloid cytokine production, we have studied the dynamics of granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) production as well as IL-1 receptor and TNF receptor expression in a clonally derived bone marrow stromal cell strain (CDCL). IL-1 alpha and TNF alpha act in a synergistic manner to stimulate G-CSF and GM-CSF production by CDCL, resulting in an increase in CSF secretion that is 250-fold greater than that observed with either cytokine alone. This synergism in protein secretion is paralleled by synergistic increases the steady-state level of GM- and G-CSF mRNA, with supra-additive levels achieved by 24 hours. Coincident with this synergistic induction of myeloid CSFs, treatment of CDCL cells with IL-1 alpha induces a 300% increase in the expression of TNF receptors. IL-1 alpha induction of TNF receptors reaches a peak after 6 hours and gradually returns to baseline level by 24 hours. IL-1 alpha does not affect TNF receptor ligand binding affinity. A kinetic study comparing IL-1/TNF synergistic induction of growth factor secretion with IL-1 alpha induction of TNF receptors shows that these events occur in parallel. In contrast with the induction of TNF receptors by IL-1 alpha, treatment with TNF alpha has no effect on either the number of IL-1 receptors expressed by CDCL cells or IL-1 receptor ligand binding affinity. Brief treatment of IL-1 alpha/TNF alpha-stimulated CDCL cells with cycloheximide before receptor induction reduces the synergistic increase in growth factor mRNA by 40% to 60% compared with cells not treated with CHX. Taken together, these results raise the possibility that IL-1 alpha cross-induction of TNF receptors may contribute to the biochemical mechanisms underlying the synergistic stimulation of G-CSF and GM-CSF production by IL-1 alpha and TNF alpha.

Genetic and immunological contributors to virus-induced paralysis

“…Also, lower-than-average levels of G-CSF were found in strains with higher paralysis levels. IL-1α acts by inducing G-CSF, which then coordinates with IL-6, to mobilize granulocytes and hematopoietic cells from the bone marrow to mediate the generation of effective immune responses against infections ( Altmeier et al., 2016 ; Basu et al., 2008 ; Caldwell and Emerson 1995 ).…”

T cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL-1 and TNFα Inflammation

“…We previously reported that G-CSF production by LLC tumor cells is dependent on signaling through the IL-1 Receptor 1 (IL1R1) 49 . IL-1α and IL-1β, both of which can signal through IL1R1, are known to synergize with TNFα through the canonical NF-κB pathway to upregulate G-CSF, CXCL1 and CXCL2 production, possibly via IL-1-induced increase in TNF receptors 55,56 . In the TME of LLC tumors, we detected both IL-1α and IL-1β, where the former is present in larger quantities while the latter is induced upon ICIs (Supplementary Fig.…”

Ο Ρόλος Των Αγγειοκινητικών Παραγόντων (Ιντερλευκίνης-6 Και -8) Στην Αιτιοπαθογένεια Των Αυτόματων Εκτρώσεων

“…Mια κυτταροκίνη μπορεί να υποβοηθά ή να εμποδίζει τη δράση μιας άλλης κυτταροκίνης 297 . Στη περίπτωση που δύο κυτταροκίνες ασκούν την ίδια δράση στο κύτταρο στόχο, τότε ασκούν συνεργική (synergistic) 298 δράση, ενώ, όταν μια κυτταροκίνη εμποδίζει τη δράση μιας άλλης κυτταροκίνης, τότε οι δύο κυτταροκίνες έχουν ανταγωνιστική (antagonistic) δράση. Φαίνεται λοιπόν, ότι οι δράσεις των κυτταροκινών επηρεάζoνται συχνά από άλλες κυτταροκίνες.…”