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IL-1R antagonist-deficient (Il1rn(-/-)) mice develop autoimmune arthritis in which IL-17A plays a crucial role. Although many studies have shown that Th17 cell differentiation is dependent on TGF-β and IL-6, we found that Th17 cells developed normally in Il1rn(-/-)Il6(-/-) mice in vivo. Then, we analyzed the mechanisms of Th17 cell differentiation in Il1rn(-/-)Il6(-/-) mice. We found that IL-21 production was increased in the lymph nodes of Il1rn(-/-) mice, naive Il6(-/-) CD4(+) T cells differentiated into Th17 cells when cultured with TGF-β and IL-21, and the differentiation was greatly enhanced when IL-1 was added to the culture. Th17 cell differentiation was not induced by either TGF-β or IL-1 alone or in combination. IL-21 induced IL-1R expression in naive CD4(+) T cells, and IL-1 inhibited TGF-β-induced Foxp3 expression, resulting in the promotion of Th17 cell differentiation. Furthermore, IL-1 augmented the expression of Th17 cell-specific transcription factors such as Nfkbiz and Batf. These results indicate that excess IL-1 signaling can overcome the requirement of IL-6 in the differentiation of Th17 cells by suppressing Foxp3 expression and inducing Th17 cell-specific transcription factors.

The CNS can be activated by both local and systemic inflammation, resulting in the manifestation of sickness symptoms. The pathways by which the CNS is activated under these two conditions, however, may differ. In this study, we injected casein into the peritoneal cavity (i.p.) or into an s.c. air pouch of mice to induce restricted local inflammation. Both routes of casein injection caused fever and reduced locomotor activity. These responses were not accompanied by the statistically significant induction of the inflammatory cytokine interleukin-1 (IL-1) in the blood and brain. Further, these responses were produced without the induction of brain cyclooxygenase-2 (COX-2), which has been implicated as an obligatory step in systemic inflammation-induced activation of the CNS. Induction of IL-1, interleukin-6 (IL-6), and COX-2, however, was found consistently at the sites of casein injection. The local inflammation-induced febrile and locomotor activity responses were blunted in animals deficient in functional Toll-like receptor 4 (TLR4), type I interleukin-1 receptor (IL-1R1), IL-6, or COX-2. Therefore, the observed febrile and locomotor activity effects appear to require local, but not central, IL-1, IL-6, and COX-2. These findings suggest that local inflammation can activate the CNS via pathways distinguishable from those mediating systemic inflammation-induced CNS activation.

In this report, we show that IL-17(+)CD4(+) and IL-17(+)CD8(+) T cells are largely found in lung and digestive mucosa compartments in normal mice. Endogenous and exogenous IL-1 dramatically contribute to IL-17(+) T cell differentiation mediated by TGFbeta and IL-6. IL-1 is capable of stimulating IL-17(+) T cell differentiation in the absence of IL-6. Furthermore, although IL-2 reduces IL-17(+) T cell differentiation, IL-1 completely disables this effect. Mechanistically, IL-1 and IL-2 play opposite roles in regulating the expression of several molecules regulating Th17 cell differentiation, including the orphan nuclear receptor ROR gamma t, the IL-1 receptor, and the IL-23 receptor. IL-1 subverts the effects of IL-2 on the expression of these gene transcripts. Altogether, our work demonstrates that IL-6 is important but not indispensable for IL-17(+) T cell differentiation and that IL-1 plays a predominant role in promoting IL-17(+) T cell induction. Thus, the IL-17(+) T cell pool may be controlled by the local cytokine profile in the microenvironment.

Pro-inflammatory cytokines, such as IL-1, IL-6, and TNF, are considered to be major mediators of osteolysis and ultimately aseptic loosening. This study demonstrated that synergistic interactions among these cytokines are required for the in vitro stimulation of osteoclast differentiation by titanium particles. In contrast, genetic knock out of these cytokines or their receptors does not protect murine calvaria from osteolysis induced by titanium particles. Thus, the extent of osteolysis was not substantially altered in single knock out mice lacking either the IL-1 receptor or IL-6. Osteolysis also was not substantially altered in double knock out mice lacking both the IL-1 receptor and IL-6 or in double knock out mice lacking both TNF receptor-1 and TNF receptor-2. The differences between the in vivo and the cell culture results make it difficult to conclude whether the pro-inflammatory cytokines contribute to aseptic loosening. One alternative is that in vivo experiments are more physiological and that therefore the current results do not support a role for the pro-inflammatory cytokines in aseptic loosening. We however favor the alternative that, in this case, the cell culture experiments can be more informative. We favor this alternative because the role of the pro-inflammatory cytokines may be obscured in vivo by compensation by other cytokines or by the low signal to noise ratio found in measurements of particle-induced osteolysis.

Proinflammatory cytokines including interleukin (IL)-1 and IL-6 exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice show a lean phenotype due to an abnormal lipid metabolism. On the contrary, it was reported that IL-6(-/-) mice exhibit obesity after 6 months of age. This study sought to assess the roles of IL-1 and IL-6 in body weight homeostasis. We generated mice deficient in IL-6 and IL-1Ra (IL-6(-/-) IL-1Ra(-/-)) and IL-6, IL-1alpha, and IL-1beta (IL-6(-/-) IL-1(-/-)). IL-6(-/-) IL-1Ra(-/-) mice exhibited a lean phenotype, similar to IL-1Ra(-/-) mice. On the other hand, IL-6(-/-) IL-1(-/-) mice became obese as early as 10 weeks of age, while IL-1(-/-) mice and IL-6(-/-) mice were normal at this age. The daily food intake was significantly higher in IL-6(-/-) IL-1(-/-) mice than in IL-6(-/-) IL-1(+/-) mice, while energy expenditure was comparable in these two strains. Acute anorexia induced by peripheral administration of IL-1 was significantly suppressed in IL-6(-/-) IL-1(-/-) mice, but not in IL-1(-/-) mice or IL-6(-/-) mice compared with wild-type mice. These results indicate that IL-1 and IL-6 are both involved in the regulation of body fat in a redundant manner in young mice.

IL-1alpha/beta and IL-6 are endogenous modulator of hypothalamo-pituitary-adrenal axis (HPAA) and are thought to play key roles in immune-neuroendocrine interactions during inflammation. Here, we show IL-1alpha induced a normal HPAA activation in IL-1alpha/beta knockout (KO) and IL-6 KO mice at 1 h; however, at 6 h HPAA activation was reduced relative to wild-type mice, indicating a role for endogenous IL-1alpha/beta and IL-6 in prolonged HPAA activation. We found that the induction of proopiomelanocortin (POMC) transcript in the anterior pituitary (AP) at 6 h in response to IL-1alpha was reduced in IL-1alpha/beta KO and IL-6 KO mice, as well as in CRH KO mice, suggesting IL-1alpha/beta, IL-6, and CRH are all required for POMC induction. The induction of CRH transcript in the paraventricular nucleus at 6 h and plasma IL-6 levels, in response to IL-1alpha, were reduced in IL-1alpha/beta KO mice. Because IL-1alpha-induced activation of signal transducer and activator of transcription 3 in the AP was also suppressed in IL-6 KO mice, we suggest that plasma IL-6 is first induced by IL-1alpha, and IL-6 activates signal transducer and activator of transcription 3 in the AP, leading to the induction of POMC in concert with CRH. Our results suggest a role for IL-1alpha/beta in the induction of POMC in the AP through the induction of two independent pathways, CRH and IL-6.

Cytokines play key roles in spontaneous CD4(+) T cell-mediated chronic autoimmune arthritis in SKG mice, a new model of rheumatoid arthritis. Genetic deficiency in IL-6 completely suppressed the development of arthritis in SKG mice, irrespective of the persistence of circulating rheumatoid factor. Either IL-1 or TNF-alpha deficiency retarded the onset of arthritis and substantially reduced its incidence and severity. IL-10 deficiency, on the other hand, exacerbated disease, whereas IL-4 or IFN-gamma deficiency did not alter the disease course. Synovial fluid of arthritic SKG mice contained high amounts of IL-6, TNF-alpha, and IL-1, in accord with active transcription of these cytokine genes in the afflicted joints. Notably, immunohistochemistry revealed that distinct subsets of synovial cells produced different cytokines in the inflamed synovium: the superficial synovial lining cells mainly produced IL-1 and TNF-alpha, whereas scattered subsynovial cells produced IL-6. Thus, IL-6, IL-1, TNF-alpha, and IL-10 play distinct roles in the development of SKG arthritis; arthritogenic CD4(+) T cells are not required to skew to either Th1 or Th2; and the appearance of rheumatoid factor is independent of joint inflammation. The results also indicate that targeting not only each cytokine but also each cell population secreting distinct cytokines could be an effective treatment of rheumatoid arthritis.

After injury to the substantia nigra pars compacta (SNpc), remaining neurons sprout to ensure normal dopamine delivery to the striatum. The consequent striatal reinnervation is highly regulated, with remaining cells sprouting so that density of dopamine terminals returns to normal. Sprouting as a result of injury is accompanied by a strong glial response; however, it is difficult to know whether this response is as a result of the injury or whether it is aiding in the sprouting. The two cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6) are important modulators of the glia response. This study demonstrates their role in regulating the sprouting of dopaminergic neurons and the associated glia response as a means to examine the role of glia in sprouting. Sprouting was induced by 6-hydroxydopamine lesions of the SNpc and by haloperidol treatment (in the absence of injury). In wild-type animals, sprouting in association with microglial and astrocyte proliferation followed partial lesions of the SNpc and haloperidol treatment. Neither treatment evoked sprouting or glia proliferation in the type I IL-1 receptor-deficient mice, whereas in IL-6-deficient mice, both treatments resulted in glial proliferation but not sprouting. We conclude that IL-1 plays a role in modulating glia proliferation and thereby guidance and trophic factors for new fibers, whereas IL-6 may be important in triggering the outgrowth of new fibers. This study demonstrates that these cytokines play an important role in plasticity and regeneration that is separate from the inflammatory response associated with brain injury.

In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)-alpha was also required, although seemingly less critically than IL-1, because a proportion of TNF-alpha-deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFalpha for bone destruction. The variability in the requirement for TNF-alpha, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes.

Previous data support the hypothesis that during inflammation, interleukin (IL)-1 beta and IL-6 are involved in fever, in activation of the hypothalamic-pituitary-adrenal (HPA) axis, and in the induction of eicosanoids. Most of the pathophysiologic effects of IL-1 beta and Il-6 are mediated by prostaglandins (PGs), modulated by other cytokines, and antagonized by glucocorticoids (GC), a final product of the HPA axis. To further test these relationships, we measured changes in body temperature using biotelemetry in mice deficient in genes for IL-1 beta and/or IL-6 (IL-1 beta knockout [KO] and IL-6 KO) following injection with lipopolysaccharide (LPS) to induce systemic inflammation or turpentine to induce local abscess. Circulating IL-6, tumor necrosis factor alpha (TNF-alpha), GC, and PGE2 were measured in these mice after treatment. IL-1 beta KO mice responded with reduced fever and IL-6 KO mice with normal fever to a high dose of LPS. In contrast, neither type of KO mice produced fever to turpentine. PGE2 levels (measured in the circulation) were suppressed in both types of KO mice injected with turpentine. IL-1 beta KO mice showed deficiency in IL-6 following turpentine, but not LPS, injection. LPS-induced increases in TNF-alpha did not differ between IL-1 beta KO mice and their wild-type counterparts, whereas IL-6 KO mice showed exacerbated LPS-induced circulating TNF-alpha. No differences were noted in plasma elevations of GC between KO and wild-type mice following injection of LPS or turpentine, indicating that IL-1 beta and IL-6 are not required for activation of the HPA axis during inflammation. Our data demonstrate that in the mouse, IL-1 beta and IL-6 are critical for the induction of fever during local inflammation, whereas in systemic inflammation they appear only to contribute to fever.

Interleukins (IL) are key mediators of the host response to infection and inflammation. Leptin is secreted by adipose tissue and plays an important role in the control of food intake. Administration of lipopolysaccharide (LPS), tumor necrosis factor (TNF), or IL-1 acutely increases leptin mRNA and protein levels. To investigate the role of IL-1 beta and IL-6 in leptin expression during inflammation, we used IL-1 beta-deficient (-/-) and IL-6 -/- mice. Mice were injected intraperitoneally with LPS or subcutaneously with turpentine, as models of systemic or local inflammation, respectively. In IL-1 beta +/+ mice, both LPS and turpentine increased leptin mRNA and circulating leptin. In contrast, neither LPS nor turpentine increased leptin levels in IL-1 beta -/- mice. In IL-6 +/+ or IL-6 -/- mice, turpentine increased leptin protein to comparable levels. We conclude that IL-1 beta is essential for leptin induction by both LPS and turpentine in mice, but IL-6 is not.

We studied the role of IL-6 and nitric oxide (NO) in IL-1 and leukaemia inhibitory factor (LIF) induced suppression of proteoglycan synthesis. Cartilage explants of patellae and femoral heads were incubated with IL-1 or LIF. Conditioned media were analysed for IL-6 activity (B9-assay) and NO content (Griess). Proteoglycan synthesis was assessed using [35S]sulfate incorporation. IL-1 dose dependently induced IL-6 synthesis and neutralizing IL-6 with antibodies did not reduce proteoglycan synthesis suppression, neither in explants nor in isolated chondrocytes. IL-6 independence was confirmed using cartilage from IL-6 deficient mice. IL-1 significantly increased NO release in normal and IL-6 deficient chondrocytes and addition of the NO synthase inhibitor, N(G)-monomethyl-L-arginine markedly alleviated proteoglycan synthesis suppression. LIF also induced proteoglycan synthesis suppression in cartilage from normal and IL-6 deficient mice, but the suppression was neither accompanied by nor dependent on NO release. Furthermore, proteoglycan synthesis suppression during experimental arthritis was similar in both normal and IL-6 deficient mice. We concluded that IL-6 is not a necessary cofactor in IL-1 and LIF induced suppression of proteoglycan synthesis. Furthermore, only the IL-1 induced suppression was mediated by NO, suggesting that inhibition of proteoglycan synthesis may occur through different pathways.

Interleukin (IL)-6, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) are considered to act as endogenous pyrogens. Because of the complex pattern of cross-inductions between these cytokines, the relative role of the central and peripheral production of these cytokines in eliciting the fever response has not yet been clarified. The purpose of this study was to determine the role of IL-6 in the fever response by making use of mice carrying a null mutation in the IL-6 gene. The intraperitoneal injections of lipopolysaccharide (LPS) (50 micrograms/kg) and recombinant murine (rm) IL-1 beta (10 micrograms/kg), respectively, failed to evoke fever response in IL-6-deficient mice, whereas the same doses of LPS and rmIL-1 beta caused fever response in wild-type mice. The fever response could be induced in the IL-6-deficient mice by intracerebroventricular injection of recombinant human (rh) IL-6 (500 ng/mouse), whereas intracerebroventricular injection of rmIL-1 beta (100 ng/mouse) failed to produce fever response in the IL-6-deficient mice. These results suggest that central IL-6 is a necessary component of the fever response to both endogenous (IL-1 beta) and exogenous (LPS) pyrogens in mice and that IL-6 acts downstream from both peripheral and central IL-1 beta.